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HAYAKAWA, S.

NOGAMI, T.

SAGAWA, I.

SAITO, H.

USUI, T.

WATARU, N.

Kyoto University Research Information Repository

Title Study on the Prognosis of Tuberculous Meningitis Treated withStreptomycin in ChildrenAuthor(s)SAGAWA, I.; USUI, T.; SAITO, H.; NOGAMI, T.;WATARU, N.; HAYAKAWA, S.CitationActa tuberculosea Japonica (1953), 3(2): 73-83Issue Date1953-12-15URL http://hdl.handle.net/2433/51770RightType Departmental Bulletin PaperTextversionpublisherKyoto UniversityStudy on the Prognosis of Tuberculous MeningitisTreated with Streptomycin in ChildrenI. SAGAWA, T. USUI, H. SAITO, T. NOGAMI,{£ )11 - fin s ;Jt- 1VJ g 'tf Hi 'tf !f .l; I~' ~N. WATARU, S. HAYAKAWAiJt 1$:::y. ¥ JI1 =it m(Received Dec. 1, 1953)Since the introduction of streptomycin as an antituberculous agent, manyreports of dramatic results in the treatment of tuberculous menigitis have appearedin the medical literature.Cures have been reported, and in fatal cases the course of illness has beenprolonged from three weeks to many months and in many instances to one ormore years.At the Faculty of Pediatrics of Kyoto Univei sity, 83 children admitted bet-ween July 1948 and March 1953 have completed treatment and most of them havebeen discharged with the diagnosis "tuberculous meningitis" written on their charts..In March 1953, we collected the results of treatment of our patients withtuberculous meningitis. The results are reported below.1) The scheme of treatmentIt is now beyond discussion that streptomycin is the most effective drug inthe treatment of tuberculous meningitis.The following scheme was adopted here; streptomycin by the intramuscularroute 0.5 g. to 1 g. according to the age and body-weight of the patient, dividedin two, morning and night, during the first month. then only half.a dose;streptomycin (not dihydrostreptomycin) intrathecally 50 mg. daily regardless ofage and weight during two months, then every other day or once or twice a week* From the Division of Pediatrics (Chief: I. Sagawa), Tuberculosis ResearchInstitute, and the Division of Pediatrics of Medical Faculty (Chief: H. Nagai)Kyoto University, Japan.74 Ichiro SAGAV,7Afor at least six months, and often longer, according to the state of the patient.PAS, Teben, Promin or INAH have been used in combination, but in thisreport, we don't mention these drugs.2) Prognosis according to the total dOS:5 of streptomycin (Table 1).As table 1 shows, no one who has received a dose less than 40 g. of strepto-mycin is clinically cured. The maximum dose of streptomycin employed inclinical cures, was 300 g., where as the dose for patients who died was only 87 g.Table 1 Prognosis according to total dose of streptomycin.I total. dose ofI.deadIalive I, curedS.M. employedless than 19 g. I 27 I 0 I 0-----20 -39g.I 11 I 2 I 040 -79g. I 13 "I 5 I 12more than 80 g.I1 I 7 I 5total I 52 I 14 I 17... _...~--~--_._.---comment: "cured" means : survival time of more than one year sines treatment 'was I begun, and at present they have no mentalof physical defects, that is, are quite healthy."alive" means: survival time has been less than' one year sincetreatment was begun, or more than one year, butwith some physical or merrtal defects.3) Prognosis according to age (Table 2).In our own series most of our cases were from 1 to 5 years old,and therate of mortality for children less than 1 year old (7 of 10 i.e., 70 %) is not sohigher than that of others. (1) (2)Table 2 Prognosis accoding to age.ageInumber ofIdead I aliveIcuredcasesII<1 ye-a r I 10(123'';) I 7C70'7~) I 2 I 1(10~~)1 '-5 years I 59C71~;) I 35C61,%) \ 10 1 13C22%)<6 years I 14(17;:'/;) I 9(64%) I 2 _J_3(21%~_4) Survival time after treatment was started (Table 3).It should be pointed out that death occurred mostly during the first six months.Of the 17 patients who have been clinically cured, 3 have been well for morethan 3 years.71,Table 3 Survival time after treatment was started.survival time alive>3 years o 23 -2 years o 4I 0I 0o2o64531183;r~ I_~~~+-~__1256-1 month1- 0.5 year<1 month____~_2_-__1_ye~r I _I5) Prognosis according to date of treatment (Table 4).We know the treatment of tuberculous meningitis will be effective only ifstarted early, but the course of tuberculous meningitis, though regular as awhole, can be long or short, and there is not always a correlation between theduration of illness at the time of the diagnosis and the condition of the child onadmission to the clinic. We can not often determine the first clinical signs, thatis, fever, headache, drowsiness, vomiting, convulsions etc., in their anamnesis,and are unable to determine the exact onset, so we select the first -signs sugges-tive of the disease.T able 4 Prognosis according to date of start of treatment.da te of startof treatment alive I cured342121third weekfirst weeksecond week~M. had been IemployedI 12 I 6 I 57%--------'-----[~~22-I_~_I_ 7 I 67%I 14 I 3 1 1 67%8--1-- 4 1---1- - ,- 3 I 50%Table 4 shows the prognosis according to the date of treatment.Contrary to our expectations and other author's assertions, (1) (2) (3) we foundthat during the first week mortality is high. Accordingly, we see the state ofconsciousness at the time of admission.6) Prognosis according state of consciousness (Table 5).We divide the state of consciousness into two groups "clear" and "not clear".We find the mortality rate in the former 52.5%, in the latter 72 %, and the rateof clinical cures in the former is 30 %, in the latter 11.6 %.The duration of an abnormal state of consciousness before treatment, insurvivors is 2.5 days, in those who died, (it is) 4.9 days.Ichiro SACAWATable 5 Prognosis according tostate of consciousness.state of Inumber of I dead I curedconsciousness cases iclear I 40 121( 52 .5,%' ) 115( 30% )not clear I 43 I31(72%) I 5(11.6%)This shows that the relation-ship between the mortality rateand the state of consciousness atthe time of admission to thehospital is much closer than therelationships between the moi tali-ty rate and duration of illness atthe beginning of the treatment.Next, we use vomiting, fever, convulsion and headache as .the first signs ofthe disease. The results are shown in tables 6, 7, 8 and 9. Table 8 is es-pecially interesting tor us, since it shows that the prognosis of the patients whohave convulsions before treatment is very bad. Loss of consciousness andconvulsions mean a bad prognosis for tuberculous meningitis.Table 6 Prognosis according to date of start o-F treatment.(using vomiting as the first sign of the disease)I 5 I 57.5%I 3 I 73.2%I cured I mortalityI 0 I 71.5%5 I 219 I 911 I 1dead I aliveI 7IIthird weekdate of start Inumber of Iof treatment cases~ first week I 33 Iseco~d ;e~kl--1-5-----+-I----;------+-----;----'------Table 7 Prognosis according to date of start of treatment.(using fever as first sign of disease)I 5 I 1 I 45.5~;I 2 I 5 I 53.2%I alive I cured I mortalityInumber of I deadcases.date oftreatmentsecond week! first week I. 11 I 51-----------;1 15 I 8third weekTable 8 Prognosis according t:l date of start of treatment.(using convulsion as date of onset)date of Inumber of! deadIaliveIcuredImortalitytreatment casesIfirst week I 6 I 6 I 0 I 0 I 100%second week , 2 I 2 I 0 J 0 I 100%third week l 2 I 2 I 0 I 0 I 100;3b. ,-77Table 9 Prognosis according to date of sta rt of treatment.(using onset of headache as :first symptom)date of Inumber of I dead IIItreatment casesalive i cured mortality-II I II i:first week 13 8 3 I 2 I 61.530---_..iI I I---------I----~----second week 6 2 0 I 4 33.3%thirk weekI2I2 i 0 I 0 I 100J';'-- -7) Complications and prognosis (Table 10).Table 10 shows that the mortality, in patients with meningitis only is 53.7 ~~,and in those with complications 71.3 9(;.T able 10 Prognosis according to tuberculous complications.disease type of Inumber of I i IItuberculosis cases deadIalive cured I mortalityi itbc meningitis only I 52 , 33I9I10 I 63.5%----_.~--+ tbc complication91 6 I 2 I 1 I 66.7'}~(not miliary) 31f miliary tu- 22 13I3I6 I 50.2'}~berculosisThe most frequent complication if naturally miliary tuberculosis (22 of 42 or52.4 9(;). The mortality of tuber culous meningitis accompanied by miliary tuber.culosis is 59.2 ~(; (13 of 22), so there is no real difference between this group andthose without miliary tuber culosis. But when accompanied by tuberculous com-plications, the prognosis is fatal (5 of 5 or 100 ~(;). In regard to tuberculouscomplications we have only 4 cases of varicella, and we found no influence onthe prognosis or on the cerebrospinal fluid.8) Prognosis according to exposure to tuberculous infection (Table 11).The presence of exposure to tuberculous infection has been estimated in 83cases as follows. (Table 11) These results do not show any clear correlationbetween exposure and prognosis.Table 11 Prognosis according to exposure of tuberculous infection.I iexposure i number of I deadI cases Ialive cured mortality9 11 53.5%5 6 72.5%known I 43 I 23--~------+----+--_----::------Iunknow~-I-~ I 299) Prognosis according to clinical symptoms and laboratory-data.To know as soon as possible, whether the streptomycin treatment is effectiveeosinophiles in their blood was 50 % inand one month later, it increased to.The percentage of monocytes did not'interest to us that the number of plas-Ichiro SAGAwAor not, we compared and examined clinical symptoms in 42 cases (25 dead and17 cured) in the first day of therapy and one month later.Contrary to our expectations, we have poor harvest, and results are pre-sented below.a) Blood picture.Anemia and leucocytosis were more severe at the begining of treatment inthe patients who died than in the others, but one month later, they returned tonormal in both groups. There were no differences in the ratio of neutr ophilesand lymphocytes.The percentage of patients who hadthe cured cases and 31 % in the others,90 % in the former and 75% in the later.differ between the two groups. It is ofmacells was different in the two groups.It averaged 13 % in those who died and 35 96 in those who were cured.h) Cerebrospinal fluid.We were unable to assign any prognostic value to the number and variety ofcells, or the concenti ation of sugar, protein or .globulin in the cerebr ospinaIfluid. It has been maintained by Enzyoziv? that the sign of hyperergie ornormergie of meningeal reaction (that is, over 200 cells and over 100 neutrophilesper ml. of cerebrospinal fluid) indicates a good prognosis. However, we can..not agree with him, because we noted this sign in 18% of those who died and in17 % of the cured cases in our series.It seems to us that an increase in the number of cells in the cerebrospinalfluid indicates a good sign for the patients, because it was seen one month afterthe start of treatment in 31 % of the cases who died, but in 649'6 those whorecovered. Improvement in the concentration of sugar, protein and globulin onemonth later, has no relationship to prognosis. For instance, improvement ofthe concentration of sugar occurred in the dead and the cured cases.c) Tubercle bacilli in the cerebrospinal fluid.We find tubercle bacilli in the web between 2 and 29 days (average time 7days) after treatment in the cured cases, and between 2 and 60 days (average17 days) in those died. This shows that the longer the tubercle bacillus is inthe cerebrospinal fluid, the worse is the prognosis. In 83 cases tubercle bacilliwere found in the web.d) General clinical condition.Prognosis was not affected by any changes in the general condition whichoccurred between the onset and one month later i.e., fever pulse and frequencyof respiration, vomiting, convulsions, stiff-neck, Kernig's sign, tendon-reflex,enlargement of liver and spleen. body-wheight, and blood sedimentation rat~.79Prognosis of tubuculous meningitis in children.c.:...:..::.-:..:.--'- -=But improvment of appetite occurred. in only 30?-6 of the patients was later diedand in 100?; of those who were cured.e) Tuberculin reaction (Mantoux reaction).Many authors (5) have maintained that the intensity of the tuberculin-reactiondecreased in proportion to recovery by streptomycin treatment, but we could notfind this phenomenon in our series.Both in those who died and those who survived, the intensity was constantthroughout the course.10) Tubercles in eye-ground (Table 12).It was of interest to us, to know how frequently we could find tubercles inthe eye-grounds in each group. We examined it for the last 20 years, and oh-tained the results stated in table 12. The number of cases is small, becausebefore 1946, our seniors had not always examined the eye-grounds of their tuber-culous patients for tubercles, even in cases of miliary tuberculosis and tuberculousmeningitis.Table 12 Relationship of type of tuberculosis and tuberculous changes(mostly tubercle) in eyeground,type of tbc changes in eye gorundtuberculosis\number of eases(+) (-)miliary tbc I 7(63.6%) I 4 I 11Itbc meningitis I 8(l3Jb) I 52 60Imiliary tbe I!I10(49%) I 16 26tbc meningitisIanother typeI 0(0%) I1 Iof tbc IIt is interesting and significant that we find tubercles in the eye-grounds morefrequently in miliary tuberculosis than in tuberculous meningitis.11) This fact suggests that tuberclous meningitis do not always occurred, even iftubercles are detected in the meninges.Table 13 shows how soon clinical symptoms subsided in the cured. cases. Inall the cases who died after a long period of survival the cerebrospinal fluid didnot return to normal. That is, when sugar concentration and cell number didnot return to normal within 6 months, the prognosis was bad.12) Permeability of streptomycin through the blood-cerebrospinal fluid barrier.This is determined by measuring streptomycin concentration in the cerebrospinalfluid 4 hours after injection of 0.5 g. of streptomycin. In survivors, . it rangestrom 0.5 gamma to 1.22 gamma, almost always over 10 gamma on the first dayso .... lchiro. SAGAW.IiTable 1:~ Time of return to normal of various clinical signs and symptoms.._-_._-------------Iclinical sings and symptoms. time vequires to return to normalI 4-8 months(sugarcell' counts I 6 --16 months'+-i lui protein, concentration 6-4 yearscJglobulin reaction I 10 months -:- 4 yearsweb I 2 .,- 6 monthsvomiting I < 1 monthheadache I <1 monthappetite I < 2 monthsfever I < 3 monthsstiffneck I < 3 monthsKernig's sign I < 3 monthstendon-reflex. I <4 monthsadmitted, and with treatment it decreases to under 0.9 gamma by the time ofdischarge. Some say that streptomycin permeability is a help in determiningprognosis and when to stop treatment, but we 'do not 'thlnk this is always so,having had a case who became worse a week after he had less than 1 gamma.It is more suitable for early diagnosis than for prognosis.13) The degree of resistance to streptomycin of tubercle bacilli isolated fromcerebrospinal fluid (Table 14).On first isolation from the cerenrospinal fluid, the tubercle bacilli are suspec-tible to streptomycin, and always inhibited by 1 gamma or less of streptomycinper ml. But they become resistant to streptomycin after treatment. . Resultsof cultures grown in Kirchner's and Oka-Katakura media are shown in Table 14.It seems to us that tubercle bacilli in cerebrospinal ft.uid did not readily developresistance to streptomycin.14) Toxic effects of streptomycin.All toxic effects were similar to those reported elsewhere.Namely, we found generalized rashes, eosinophilia, albuminuria is somecases, and one child died ?f agranulocytosis. In one case a patient becamedeaf while under treatment, in another after treatment, and a third child becamehard of hearing. It seems tous that vestibular disorder is clinically the mostsignificant side effect of streptomycin.15) The effect of streptomycin therapy.31 patients are alive out of 83 tr'eated, 17 of the 31 are in good general81Prognosis of tubuculous meningitis-in children,-----=--------_-=-:::~Table 14 The degree of resistence of tubercle bacilli isolated from cerebrospinal fluid.the number Resistance of [case number S.M. dose of days use of isolated prognosis(grams) S.M. was S.M. tubercle bacilliemployed I (r)1 64 160 i.m.z> lZ.0r I deadi.t.o1 70 190 'I 12.0 dead2 26 40 'I 1.4 dead2 48 140 'I 111.0 dead3 69 139 II 5.0 dead4 12.5 25 II 4.0 cure5 5 10 II 12.0 II6 42 170 i.m. 4.0 alive7 15 60 II 1.0 II8 10 30 1/ 5.0 deadb.. i.m.j intramuscular injectiono i.t.: intrathecal injectioncondition without any clinical manifestations of illness.The value of streptomycin therapy in meningitis can perhaps be judged mostcorrectly by the rate of survival and the physical and mental condition of sur-vivors, so that, we distinguished complete cures from survivous. Cures haveno physical or mental defects, namely, they are quite healthy. (Table 15) Wefind the mortality rate of tuberculous meningitis is considerably high (60-8096 ap-proximately 70 %) in our country compared with the rate in foreign countriesE. Lincoln"? has reported the mortality as less than 30% and Cocchi-P only 1596 inhis later series. Less good results (50 %) have been obtained by Debe.The best results that we know are those of L6ffler( 8) which is less than 10 76.This difference is explained partially by the different method of chemotherapy.We must endeavor to increase the number of cures of tuberculous meningitisdevising ways to employ streptomycin combined with other antituberculous drugs,~Table 15 Observation of cases cured.--_.. -- ---- - ---- --- -._--- ------ ---- -----_.------ ----------- ---- -- --~-total dose total numbersurvival months Iage of S.M. of times of time since S.M. patients state at presentcase no. (ye.ars, months) employed S.M. intrathecal treatmentI(grams) injection (months) was stopped'"--- -'_.-----I 3,10 40.0 85 times 48 months ·37 months quite healthy; not very good student2 3, 5 56.0 69 43 36 // ; very good student3 2, 1 105·9 119 42 28 II ; varicella: II months after end of treatmentpertussis: 12 months4 7, 5 42.3 106 36 28 // ; not very good student-----_.-----;. measles and varicella: 16 months after5 0, 7 62.0 34 34 26 1/completing treatment6 9, 3 70.0 48 30 22 // ; first in'his class7 I, 5 86.0 82 27 17 1/ ; pertussis: 2 months after completing t reamerrt8 12, 1 49.0 86 26 16 quite healthy9 4,11 300.0 76 25 2 // ; very good student---10 1, 6 70.0 51 23 17 quite healthy11 1, 9 61.0 51 22 16 1/ ; pertussis: 6 months after completingtreatment12 3, 4 70.0 69 20 12 quite healthy13 2, 0 74.0 87 19 12 quite healthy14 4, 6 EO.O 124 15 8 quite healthy----15 . 5, 1 EO.O 150 15 9 quite healthy .",16 1~ 3 50.0 45 13 0 quite healthy17 5, 3 76.0 67 13 5 quite healthy----- ------- --,-- -~--_._-_.._----,-~--_._------------------ --------------- '---------_._--~~G~CI'.l~~~Prognosis oj tuberculous meningitis in chsld ren,References0) KOCH, I.: Beit r. Klin. Tbk. 106, 338 (951)(2) DEBRE, R.: Amer. Rev. Tbc. 65. 168 (1952)(3) CALNAN, W. L.: Brit. J. Tbc. 45, 153 (1951)(4) ENZYOZI, M.: Journal for Pediatric Praxis Japan, 15, 361 (1952)(5) LEITNER, .T., et a1.: Schweiz. med. Wschr. Jan. 27, Nr. 4, 87 (1851)(6) LINCOLN, E.: Amer. J. Dis. Child. 82, 655 (1951)(7) COCCI, C.: Arch. Ped. 68, 301 (951)(8) LOFFLER, W., et a1.: Dtsch. med. Wschr. Nr. 17, 542 (1952)83

Study on the Prognosis of Tuberculous Meningitis Treated with Streptomycin in Children

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Study on the Prognosis of Tuberculous Meningitis Treated with Streptomycin in Children

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