complications of meningitis

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COMPLICATIONSOF MENINGITIS~BY WILLIAM . NYI~IAN, M.D., PH.D.

~ANDFREDERICK~ICHARDSON,V~.B., M.R.C.P.t

Department of Pediatrics, The 7ohns Hopkins University School of Medicine,Baltimore, MarylandThe development of methods of treatment for fatal diseases may per-

mit the recognition of concomitant or late sequelae which were previouslyrare or unknown. The complications of pyogenic meningitis represent adramatic example of this principle. Therapeutic attack on this diseasebegan in 1891 with the discovery of lumbar puncture by Quincke (1), mak-ing possible the establishment of etiological diagnoses during life. The de-velopment of antimeningococcal serum by Flexner shortly thereafter (2, 3)began an alteration of the mortality of the disease, which has now beendramatically altered by the development of chemotherapeutic and anti-biotic agents.

The successful treatment of purulent meningitis is one of the mostexciting and satisfying responses in clinical medicine. However, it has be-come apparent that complete recovery is not the rule, and a certain num-ber of fatalities continue to occur. Alexander (4) commented in 1954 thatno significant decrease in mortality had occurred in pyogenic meningitisin 10 years and that among the survivors at least 12 per cent had evidenceof major cerebral damage. It is possible that the therapeutic advance onthe disease has reached a plateau. Further therapeutic advances may re-quire a close investigation of the consequences of meningitis and the de-velopment of methods for their prevention or early treatment.

The complications of purulent meningitis will be the subject of this re-view. Tuberculous meningitis and aseptic meningitis will be consideredwhere the principles illustrated are applicable to the problem of pyogenicmeningitis.

MORTALITYThe most serious complication of any disease is death. In meningitis,

a relatively high mortality rate is a continuing problem despite the remark-1 Thesurvey of the litel~ture pertaining to this review was concluded n August,

1962.1 The ~ollowing abbreviation will be used: ADHantidiuretic hormone).8 Faculty Research Associate of the AmericanCancer Society.4 Director, Diagnostic and Evaluation Center ~or HandicappedChildren, JohnsHopkins Hospital. Work related to this review (F.R.) was supported in partgrants from the Joseph P. Kennedy, Jr., MemorialResearch Fund and the NationalInstitutes of Health (Grant No. B3877).

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244 NYHAN & RICHARDSONable advances in therapy. In 1956, bacterial meningitis was the sixth mostcommoncause of death in children in the United States (5). Amongpa-tients over 40 years of age, mortality rates in pneumococcal meningitis re-main in the range of 50 to 80 per cent (6).

Alexander (4) reported an overall mortality of 13 per cent in patientswith pyogenic meningitis treated from 1944 to 1954 at Babies Hospital.An identical figure of 13 per cent was obtained in a series of 328 patientsseen from 1949 to 1959 at the Harriet Lane Home (7). Among the com-monforms of meningitis, the highest fatality rates have been seen in pneu-mococcaI meningitis. Alexander (4) observed a mortality of 25 per centin pneumococcal meningitis, while the corresponding values for meningo-coccal and Hemophilus influen~ae meningitis were 15 per cent and 7 per cent.Levinson (8) reported similar experience in over 1000 patients, with mor-tality rates of 25 per cent in pneumococcal, 10 per cent in meningococcal,and 9 per cent in Hemophilus influen~ae meningitis. The influence of treat-ment is reflected in mortality rates of 100 per cent, 90 per cent, and 100per cent, respectively, for these three forms of meningitis before the avail-ability of antibacterial treatment (8).

In pneumococcal meningitis, the influence of age on mortality is par-ticularly pronounced. In infants and children under 10 years, Spink (6)found a mortality of 19 per cent which is consistent with the data reportedabove from pediatric sources. In the years from 11 to 20, the mortality was14 per cent, and from 21 to 40 the mortality declined further to 8 per cent.However, with advancing age thereafter, the prognosis worsened. After 41years, the mortality was 53 per cent. The majority of pediatric patientswith pneumococcal meningitis are less than six months of age (9). Mostof the older children and adults with pneumococcal meningitis have puru-lent otitis media (9). In Spinks series, 33 per cent had otitis (5). Mortalityrates as high as 47 per cent observed in patients with meningitis and chronicsuppurative otitis (10) may reflect this relationship with the infecting or-ganism as well as difficulties in eradicating infections in the presence oialtered anatomy.

Meningitis in the first month of life is associated with a particularlypoor prognosis, with mortality rates approximating 75 per cent (11, 12),This high fatality relates to the difficulty of diagnosis in this age group(13), as well as to the resistance of the host. Meningitis and high mortalitycaused by organisms not commonly pathogenic, such as the coliform or-ganisms (4, 14, 15), are seen almost exclusively in this period of life. Sim-ilarly, Flavobacterium meningosepticum was associated with fatality in10 of 14 newborn infants with meningitis (16).

Mortality rates are also often high when meningitis is produced by cer-tain uncommonly encountered organisms. Listeria monocytogenes ha.,caused death in as many as four out of eight patients (17). In Salmonellameningitis, approximately 88 per cent .of reported patients have died (18,.19).


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COMPLICATIONSF MENINGITIS 245ACUTE COMPLICATIONS

Meningitis is a complication of septicemia, and, as such, it may becomplicated by other manifestations of sepsis (13). In the afebrile patientundergoing successful treatment of meningitis, elevation of the pulse mayindicate infection in a closed space as in septic arthritis or osteomyelitis.Early diagnosis and adequate local treatment of these complications mayprevent permanent disability, and may prevent recurrence of septicemia. Onthe other hand, pneumonia or primary peritonitis would be expected to re-spond more readily to antibiotic therapy than would meningitis. Brain ab-scess may rarely be found in association with meningitis (20).Epidemic meningitis.--Epidemic meningitis is a social complication ofmeningitis rather than an individual complication. The occurrence of men-ingococcal infections in epidemics is well recognized, as is the relative rarityof epidemic transmission of other forms of nleningitis. The transmissionof meningococci is via the respiratory route, and control of spread to con-tacts is carried out by culture or sulfonamide treatment. An epidemic ofmeningitis in newborn infants has recently been described (16, 21) in whicha different form of transmission was responsible. Meningitis caused byFlavobacterium meningosepticum was observed in 14 cases, 10 of whomdied, and nasal colonization was found in 30 more newborns. It was foundthat this organism contaminated a leaky trap in a nursery sink, and fol-lowing repair of the sink new cases were not observed.Subdural effusions.--The occurrence of coll6ctions of fluid in the sub-dural space is a complication of pyogenic meningitis whose recognition hasbeen associated with the development of effective methods of antibacterialtreatment. Yet this complication probably did occur infrequently prior tothe availability of antibacterial agents, for a certain number of infantswith meningitis are found to have effusions at the time of admission to thehospital. Furthermore, Penfield (22) reported a patient with a subduraleffusion and chronic otitis media in 1923, and Spitz, Pollak & Angrist (23)described the findings at autopsy in two patients with untreated meningitiswho developed subdural empyemawithout evidence of disease in the earsor sinuses. Nevertheless, it was not until the report of McKayet al. ap-peared (24) that it became evident that a new syndrome was resulting fromthe successful treatment of bacterial meningitis. Accumulations of sterilefluid were observed in the subdural space in a significant number of pa-tients with meningitis caused by Hemophilus influen~ae, type 13. It soonbecame evident that subdural effusions could complicate any type of bac-terial meningitis.

The mechanisms by which collections of subdural fluid occur in a certainnumber of patients with meningitis is not entirely clear. It seems likely thatthere are a number of ways in which the process may be initiated. Ultimately,the pathogenesis of the effusions is probably quite similar, regardless of theinitiating cause. In fact, the fluid obtained from a well-developed postmen-ingitic subdural effusion looks just like that obtained on repeated taps from a


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246 NYHAN & RICHARDSONtraumatic subdural hematoma (25) or from an effusion which followspneumoencephalography (26). Purulent subdural fluid is occasionally foundearly in the course of meningitis, particularly in patients dying beforeadequate treatment can be initiated (7, 23, 27). However, it is not usuallypossible to distinguish infected from noninfected subdural effusions in pa-tients with meningitis, and the conditions are generally considered together.In addition, it is probable that some patients with meningitis develop sub-dural hematomas. Ingraham & Matson (28) have pointed out the importanceof the delicate veins which bridge the cerebral cortex to the large duralvenous sinuses in the development of traumatic subdural hematoma. Rapidshifting of intracranial contents in other situations might be expectedto result in the tearing of these veins. For example, subdural hematomahasbeen reported as a complication of operations for hydrocephalus (29).Similar shifting of intracranial contents may occur in the treatment ofsubdural effusions through the removal of very large quantities of fluidby subdural tap or at surgery, with the subsequent development of newsubdural lesions (7). Williams & Stevens (30) have suggested thatdural effusions in patients with meningitis have resulted from rupture ofthe bridging veins following shift of the cranial contents which resultfrom the removal of large amounts of fluid at the time of lumbar punc-ture. Appropriate caution in the removal of cerebrospinaI fluid has beenengendered by this concept; however, evidence to support the hypothesishas yet to be presented. It seems likely that effusions in certain patientswith pyogenic meningitis begin with subdural abscesses, while others com-mence with subdural hematomata. However, the majority appear to beserous effusions from their onset. Arnold (31) reported a patient in whomelectrophoretic analysis of the subdural fluid revealed a pattern similar tothat of the serum. These data suggest an altered permeability of membranesin meningitis, promoting the effusion of fluid from vessels into the sub-dural space. The pathogenesis of this problem has been systematicallystudied by Gitlin (32). The concentrations of albumin and gammaglobulinwere determined immunochemically in patients with subdural accumulationsof fluid in bacterial meningitis, following pneumoencephalography, andfollowing trauma. In all three conditions, the levels were quite similar, andin each the ratio of albumin to gammaglobulin in the subdural fluid wasconsiderably higher than in the serum. These data suggest that the basicmechanism by which fluid accumulates in all of these conditions is an ef-fusion of fluid through damaged or inflamed capillary walls.

The incidence of subdural effusion in patients with pyogenic meningitisis of clinical importance for it has therapeutic implications in the manage-ment of meningitis. McKay, Ingraham & Matson (33) reported an ap-proximate 50 percent incidence of effusions in 50 patients with purulentmeningitis. Similarly, Smith, Dormont & Prather (34) found subduraleffusions in 20 of 43 patients with meningitis under 2 years of age. Thesedata would suggest that diagnostic subdural taps be performed regularlyin patients recovering from purulent meningitis. On the other hand, in a


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COMPLICATIONS OF MENINGITIS 247number of reports of experience with meningitis (35 to 38) in generalwell as one dealing with the sequelae of meningitis (39), the incidenceeffusions was considerably lower, ranging from 6 to 17 per cent. These dataimply that routine subdural taps may not be necessary in patients withmeningitis. However, in the largest of these series, the incidence of effu-sions in those patients whose meningitis was caused by Hemophilus influ-enzae was 50 per cent (36). Benson, Nyhan & Shimizu (7) have recentlyreported a study of subdural effusions in patients with meningitis, in whichpatients found by subdural taps not to have effusions were studied as con-trols for those in whom ffusions were found. The 67 patients found to haveeffusions comprised 21 per cent of the 328 patients with purulent meningitisadmitted during the period of study, but they were 62 per cent of the pa-tients in whom aps were performed. These data indicate that the incidenceof subdural effusions is related to the vigor with which they are sought.

A number of clinical manifestations have been observed in patients withsubdural effusions which may be useful as indications for investigation ofthe subdural space (7, 33, 40). Arnold (27) has pointed out that infectedsubdural effusions may occasionally be recognized by the presence oferythema, induration, and local heat in the area of the anterior fontanel.A recurrence of fever in a patient under treatment for meningitis appearsto be a good indication for exploration of the subdural space (7). Con-vulsions, recurrent meningitis, persistence of fever, coma, ir/itability,vomiting, or positive cerebrospinal fluid cultures after 48 hr of treatment,persistent opisthotonus or bulging of the fontanel, gross neurological find-ings, or signs of increased intracranial pressure may all be helpful in sug-gesting the presence of effusion. However, these findings are present inpatients without effusions and absent in a significant number of those witheffusions. Transillumination of the skull of infants may occasionally indi-cate the presence of effusions. :Electroencephalography may reveal the pres-ence of a subdural effusion (20, 41) but a negative electroencephalographicexamination does not rule out this lesion (7). The inadequacies of the in-dications currently employed for the performance of subdural taps inpatients with meningitis are illustrated by the discovery of 34 per cent ofa series of subdura! effusions by the performance of routine subdural tapsin patients with meningitis (7). McKay 42) has commented that patientsin whomsubdural effusions are demonstrated on routine taps may be pre-symptomatic rather than asymptomatic. This would seem to be a likelyhypothesis; however, if the patient could be spared the development ofsymptoms of the sort observed with effusions and possible attendant dam-age to the brain, this would appear to be worthwhile. The routine perform-ance of subdural taps in patients with meningitis and open sutures seemsto have much to recommend it (7, 9). Data on subdural effusions in pa-tients over 18 months of age is sparse, but effusions do occur in such pa-tients, and one is dependent upon the development of clinical manifesta-tions of effusion for the performance of diagnostic trephination.

Meningitis is caused by H. influenzae, type B, more commonly than by


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248 NYHAN & RICHARDSONany other organism in the age group in which subdural effusions are com-mon; although this organism is found with equal frequency in patients withand without effusions (7), the greatest number of subdural effusionsfound in patients with H. influenzae meningitis. Infants with pneumococ-cal meningitis are more likely than not to have subdural effusions, whileeffusions are uncommon n meningococcal meningitis. Subdural effusionsmay also occur in tuberculous meningitis (43) and in aseptic meningitis(44).

The treatment of subdural effusions in patients with meningitis is thesubject of considerable divergence of opinion. McKay, Ingraham & Matson(33) found membranes in the majority of their patients and recommendedthat they be treated with initial decompression by subdural taps, followedby trephination in the search for membranes, with removal, via craniotomy,of membranes found. Williams & Stevens (45) have recommended craniot-omy in all cases. Yet, a number of physicians have observed that repeateddrainage by subdural taps has resulted in a drying up of the effusion andapparently complete remission (9, 34, 39, 40). Most patients have beentreated in this way. MeKay(42) continues to recommend trephinationall cases, and this regimen is supported by finding membranes in a few in-dividuals in whomoperation was performed after drying of the subduralspace had been demonstrated folIowing treatment by repeated taps (45, 46).However, Smith & Landing (47), in a study of pathologic changes infatal cases of Hemophilus influenzae meningitis, found only one subduraleffusion, suggesting that most effusions are handled successfully clinically.Furthermore, one patient reported by these investigators was treated for sub-dural effusion by repeated aspiration for 13 d~tys; 19 days later, he devel-oped sepsis and died. At autopsy there was no evidence of subdural effu-sion or membrane. Similarly, in a series of patients with subdural effu-sions in which the majority was treated by aspiration of fluid alone (7),the incidence of death or late sequelae was no greater than that found ina group of patients with meningitis without effusions. This question couldbest be answered by a controlled study, with careful follow-up of patientsover a number of years. However, available data appear to indicate that,in patients with postmeningitic subdural effusions in whom he subduralspace can be readily dried by repeated drainage by subdural taps, a con-servative approach without further neurosurgical procedures would beadvisable. This is consistent with published pediatric (9, 48) and neuro-surgical (49) opinion. Certain other aspects of management appear cIearintuitively and are supported by the results of follow-up examinations (7).In patients treated by subdural taps alone, the prognosis is better in thosein whom vidence of a dry subdural space is the indication for terminationof therapy. Volumes of fluid greater than 15 to 30 ml should not be re-moved at any single subdural tap, and further examination through burrholes should be carried out whenever subdural taps continue to yield fluidreadily after two weeks of repeated drainage. A high incidence of permanent


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COMPLICATIONS OF MENINGITIS 249sequelae was found in patients in whom membranes were seen and notremoved, while those in whom membranes were excised did very well inspite of previously stormy courses. Therefore, subdural membranes, whenfound, should be removed.

Hyponatremia.--The recognition of abnormalities in body physiologyor biochemistry that may produce central nervous system manifestations isdifficult in the presence of underlying central nervous system disease. Yet,such alterations may contribute to acute morbidity and mortality as wellas to the development of permanent sequelae of treatable diseases. An ex-ample of this concept is the acute symptomatic hyponatremia observed inpatients with infections of the central nervous system (50). Similar prob-lems may as yet be unrecognized.

A relationship between the concentration of sodium in the serum andthe presence of central nervous system disease was pointed out by Peters,Welt and colleagues (51, 52) with the description of a cerebral salt-wastingsyndrome. The patients described were characterized by an inability to re-duce the excretion of salt in the urine despite marl~ed depression in theconcentrations of sodium in the serum. These patients presented signs oftrue salt depletion, including clinical dehydration, hypotension, and azotemia,and they responded to the administration of large quantities of sodiumchloride with a disappearance of symptoms and the restoration of serumconcentrations. This syndrome has not been described in patients with men-ingitis.

Hyponatremia without dehydration and azotemia was described by Ny-ban & Cooke (50) in patients with acute infections of the central nervoussystem. In the initial report, seven episodes were reported in five patients,four of whomhad purulent meningitis; one had measles encephalitis. Sub-"sequent experience has indicated that this is a relatively common ompli-cation of pyogenic meningitis, occurring also in tuberculous meningitis(53). A lowered concentration of sodium in the serum may result froman increase in the volume of extracellular water as well as from a decreasein the amount of sodium in the body, and in patients with this syndromethere appears to be a relative increase in the proportion of water to thatof sodium. Abnormal losses of sodium from the skin or gastrointestinaltract have not been found, and a balance study revealed extremely lowquantities of sodium in the urine. Oliguria was documented during theperiod of hyponatremia, and this has been observed regularly. It has beenpostulated that the inappropriate release of ADH esults in an inability toexcrete normal loads of water and leads to water intoxification.

The clinical manifestations of acute water intoxication are indicated inTable I. Milder symptoms such as headache, vomiting, and muscle crampsmay progress to convulsions, coma, cerebral edema, and death (54, 55).Papilledema and retinal hemorrhages (56) have been seen. Many of thesesymptoms would be difficult to recognize in patients with meningitis orwould tend to be attributed to the meningitis. However, among the patients


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250 NYHAN & RICHARDSONstudied, restlessness, irritability, and convulsions, although not specifichave been useful in suggesting the presence of hyponatremia. The seizure~respond poorly to the usual anticonvulsant medications. The condition i.,best diagnosed by the regular determination of the concentrations of electrolytes in the serum.

A third type of hyponatremia seen in diseases of the central nervou~system has been described as asymptomatic. Chronically low levels of sodium in the serum have been observed in patients with tuberculous meningifts (57, 58, 59) and a variety of other central nervous system disease~(60, 61, 62). Asymptomatic hypo-osmolarity has also been describedpulmonary tuberculosis (63), pneumonia and other infectious diseases (6465), and in bronchogenic carcinoma (66, 67, 68). Patients with this formhyponatremia excrete large quantities of sodium in the urine and, unlik,those with the other two types, they are not benefited by the administratio~of sodium chloride. Large loads of sodium administered therapeuticallyexcreted in the urine and hyponatremic levels are maintained in the serumThe hyponatremia in this syndrome is related to the retention of waterand an inappropriate secretion of ADH as been invoked to explain it. Restriction of fluid in these patients results in restoring the normal concentrations of sodiur o extracellular volume and the ability of the kidneyconserve sodium.

Hyponatremia always indicates a relative excess of water over solub(69) and, in the absence of hypovolemia and azotemia, it is difficultvisualize such a defect without an inappropriate excess of ADH. A modefor these clinical conditions was provided by Leaf and associates (70)experiments in which sustained levels of antidiuretic activity were maintained in normal individuals by the administration of vasopressin tannat,in oil. When given a constant water intake, these individuals responde(with increased weight and decreased levels of sodium in the serum.vasopressin administration was continued, large urinary losses of sodiunand chloride were observed on the third day. The renal loss of sodium

TABLE IMANIFESTATIONS OF ACUTE HYPONATREMIA WATER INTOXICATION

HeadacheNauseaMuscular rritabilityComaBlood pressure elevationPapilledema, retinal hemorrhagesConvulsions, continuous or recurrentPoor response to usual anticonvulslve

medicationRecovery ollowing repair of the concentra-tion deficit

RestlessnessWeaknessIncoordinationApnea, periodic breathingEdemaminimal; especially perlorbita


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COMPLICATIONS OF MENINGITIS 251interpreted as a homeostatic response to the overexpansion of fluid volumeand could be prevented by restriction of fluids during the period of vasopres-sin administration.

Continued administration of vasopressin has resulted in a steady-statein which water and sodium balances are restored at levels of persistent hy-ponatremia (69). It has begun to appear, therefore, that acute symptomatichyponatremia, the second type described above, and asymptomatic hypo-natremia, the third type, may be two stages of the same process. Acutesymptomatic hyponatremia represents water intoxication occurring mostcommonly during the early days of ADI-I secretion in conditions such asacute pyogenic meningitis. Asymptomatic hyponatremia develops moreslowly in general and is observed in conditions such as tuberculous menin-gitis and bronchogenic carcinoma. Acute symptoms of water intoxicationoccasionally occur in complication of chronically asymptomatic hypona-tremia (53, 60, 62), and dilutional hyponatremia without significant saltwasting has been seen in bronchogenic carcinoma (68). However, theasymptomatic variety o~ hyponatremia has not been observed in pyogenicmeningitis.

Recurrent meningitis.--A second attack of meningitis in the same pa-tient is an unusual complication and one in which exhaustive investigationfor an underlying cause is indicated. The difficulties which may be encoun-tered were illustrated by Spitz and colleagues (71) in a boy who had20 attacks of meningitis and 4 surgical procedures before the route of in-fection was discovered and obliterated.

Recurrent meningitis may occasionally reflect the nature of the infect-ing organism. An ability to lie dormant in ct:yptic loci for shorter or longerperiods after apparent eradication as observed with Salmonellc~, or rela-tive insensitivity to antibiotic treatment, may promote recurrent attackswith the same organism. However, the most common cause of recurrentmeningitis is the pneumococcus (6, 72), and often different serologicaltypes are involved. This suggests that either local or general factors in-volved in the resistance to meningitis are faulty in such cases. Recurrentpneumococcal meningitis has been reported among the severe infectionsseen in splenectomized children (73). Susceptibility to infection and fre-quent pneumococcal infections are also observed in patients with congenitalabsence of the spleen, agammaglobulinemia (74), and multiple myeloma;thus patients with recurrent meningitis should be investigated for theseconditions.

Recurrent meningitis may occur in the presence of congenital dermalsinuses or embryonal rest-cell tumors of the nervous system, in which theexternal orifice of the sinus may be obscurely located anywhere from theperineum (75) to the occiput (76). Other congenital abnormalities suchaqueductal stenosis and cervical vertebral anomalies (77) may be associatedwith recurrent meningitis. Chronic otitis media and mastoiditis may pro-vide a focus for recurrent meningitis (6) or a subdural membrane maypromote recurrence of meningitis (7, 50). Manyof the cases appear to


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252 NYHAN & RICHARDSONposttraumatic (78). However, the fistula through the dura may be difficultor impossible to locate through roentgenographic techniques (76, 79, 80).Multiple attacks of bacterial meningitis may be the only indication of anabnormal connection between the nasopharynx and the meninges, andneurosurgical exploration may be required to demonstrate it (80).

CHRONIC COMPLICATIONSNeurologic and intellectual sequelae.--It has long been recognized that

patients recovering from meningitis may have neurological sequelae, suchas hydrocephalus, deafness, blindness, mental deficiency, convulsions, orother evidences of damage to neural tissue. The types of residua reportedby Ross (81) following meningococcal meningitis are typical of the sequelaewhich may follow purulent meningitis. Abnormalities such as hemiparesis,blindness, deafness, electroencephalographic abnormalities, and diffuse"brain damage" were found in 43 per cent of patients followed. Only 51 of252 patients returned for follow-up. However, Benson et al. (7) foundsome evidence of central nervous system damage in 32 per cent of patientssurviving the acute illness in a study of all forms of meningitis in whichan 80 per cent follow-up was obtained. Patients recovering from meningi-tis caused by Hemophilus influenzae were studied by Bloor and associates(82), who reported that 31 per cent of the survivors had minimal neuro-logical signs such as a positive Babinski sign, and 38 per cent had majorneurological problems such as gross developmental retardation, hydro-cephalus, and hemiparesis. Seizures occurred in 71 per cent of survivorsduring the acute illness and persisted in 1.4 per cent, all of whomwere inthe severely damaged group. Benson and co-workers (7) reported seizuresin 14 per cent of patients with purulent meningitis and subdural effusionsfollowed, but in only one of 28 patients without effusions. Similarly, Berg-strand and colleagues (83) noted serious sequelae in 15 of 77 patients seenin a follow-up study of children surviving purulent meningitis. Among he15, five were grossly retarded, five had seizures, seven had pareses, fivehad deafness, six vestibular damage, three ataxia, and two hydrocephalus.

Information as to intellectual impairment following meningitis is con-siderably more elusive than that relating to neurological damage. Intel-lectual damage other than severe mental deficiency has seldom been docu-mented, or studied carefully. A follow-up study in which developmentalinformation was obtained was carried out by Crook, Clanton & Hodes (84)in 64 of 87 patients who survived meningitis resulting from H. influenzae.In 52 patients who were apparently completely well, developmental examina-tions could be performed in 21, of whom en were found to be below aver-age. Of these, four were in the dull or defective range. In the group of87 patients, there were also four patients with severe mental deficiencythat was recognizable at the time of discharge following acute meningitis.

A study carried out by Wolff (85, 86) on 179 patients treated at theBirmingham Childrens Hospital, England, who survived meningococcalmeningitis during the years 1937 to 1949, is of particular interest and im-


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COMPLICATIONS OF MENINGITIS 253portance. Eighty per cent of the original cases were reexamined personallyand intelligence tests were performed on 134 of the 138 children seen (inthree instances severe deafness and, in one, lack of cooperation preventedthe performance of the tests). The ages of patients ranged from 2 to 21years. The results of the intelligence testing are shown in Figure 1. Theintelligence quotients observed in three different age groups have been con-trasted with those of a group of normal children. The data charted are thepercentage of the total children in each of the intelligence levels on the ab-scissa.

Wolff concluded that an attack of meningococcal meningitis during thefirst six months of life (Fig. la) has a profound effect on the intelligenceof the child. In this age group, the majority were below the average rangeand approximately one-fifth were severely mentally defective. In childrenbetween six months and one year (Fig. lb), an effect of meningitis on thesubsequent intelligence was still readily discernible, but a number of chil-dren were of average intelligence or better and severe mental defect wasuncommon. In the 81 children whose acute meningitis occurred after theage of one year (Fig. lc), the mean intelligence quotient was 96.8 whichdid not differ significantly from the normal mean of 100. It was concludedthat an attack of meningococcal meningitis over the age of one year, withfew exceptions, does not affect the intelligence or lowers it only slightly.

The usually rapid onset of meningococcal meningitis and its equallyrapid resolution or response to adequate therapy, suggests that survivors ofmeningitis resulting from other organisms of less dramatic presentation andresponse such as H. influen~ae, D. pneumoniae, and M. tuberculosis, maycause even more damage to the brain and the intellect. It appears reasonablethat a continuum of neurological and intellectual damage probably existsbetween the fatal cases, the survivors with neurological impairment, andthose patients who appear to have made a complete recovery. By analogy,those organisms associated with a high mortality rate are likely also to beassociated with a high incidence of neurological damage and mental impair-ment.

Comparison of these data with the end results of tuberculous meningitismay, therefore, be useful. The long-term results in 100 children survivingtuberculous meningitis out of 170 treated have been studied by Lorber (87).Seventy-seven appeared to be normal and 23 had various sequelae rangingfrom minimal facial weakness to profound intellectual and physical disor-ganization. Formal intelligence tests given to all children revealed six whowere severely retarded. Of the 94 remaining patients, 65 had an IQ of 100 orless. The most severely affected children were two years of age or less onadmission. Of the six grossly retarded children, four had hemiplegia andtwo quadriplegia, and in this group convulsions, blindness, optic atrophy,and sexual precocity occurred. Seven children had an IQ of approximately120 or more.Behavioral and personality changes following meningitis.--Meningitis is


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COMPLICATIONS OF MENINGITISoften accompanied by an encephalitis which, on occasion, may dominate theclinical picture. Personality defects and psychiatric symptoms may occurafter almost any form of meningitis. Ballard & Miller (88) studiedmen seen in a Royal Air Force Center who had had meningitis three tosix months prevously, and found 53 who complained of such symptoms asinsomnia, dizziness, difficulty in concentrating, muscular pains, and back-ache. The authors regarded these symptoms as psychosomatic reactions be-cause there seemed to be a relationship to neurotic predisposition. This as-sumption, however, does not preclude the possibility of damage to neuraltissue in a previously neurotic patient that may result in new symptoms.The problem of compensation may contribute to symptomatology, but, inchildren, Pai (89) described personality defects, intellectual deterioration,conduct disorders, instability, and vulnerability to stress as sequelae tomeningococcal infection, and other authors have ascribed similar residuato meningitis ascribed to other organisms with or without frank neurologi-cal sequelae (90).Intellectual sequelae of asepEc men~ngitis.--Whether or not asepticmeningitis is a benign event would seem to depend on the nature of the in-vading organism. Gibbs et al. (91) reported electroencephalographic studieson 158 patients with aseptic meningitis in whom44 per cent of childrenand 23 per cent of adolescents showed slowing of cortical activity. In allbut two cases, the electroencephalogram returned to normal.

Anicteric leptospiral meningitis is being reported with increasing fre-quency. Cargill & Beeson reported abnormal cerebrospinal fluid in approxi-mately 85 per cent of cases of Wells disease (92). Richardson & Battaglia(93) observed intellectual and behavioral sequelae of a postencephalitictype persisting after recovery from meningitis caused by Leptospira cani-cola.Dec~fness following meningitis.--Deafness deserves special mention asa sequel to meningitis because of its frequency and severity. It may besevere enough to cause loss of useful speech in an intelligent patient (87,94). Wolff found that 20 per cent of survivors of meningococcal meningitishad impaired hearing, and 3 of these 26 children required admission to aschool for the deaf (85, 86). A detailed examination of six children withsevere postmeningitic deafness revealed that although they might takenotice of sound they were unable to recognize its meaning and had auditoryagnosia (95). Loss of hearing may have occurred more commonly withthe use of intrathecal streptomycin but, certainly, deafness occurs in pa-tients with purulent meningitis in whom here is no exposure to strepto-mycin. Nearly one-third of severely deaf children attending schools forthe deaf in a representative area of England were classified recently ashaving deafness following an infectious illness (96). Of 69 patients bornbetween 1945 and 1954, 51 had had pyogenic or tuberculous meningitis(96), On the other hand, of 61 patients who had had pyogenic meningitisand who were specifically studied for hearing defect at follow-up, onlytwo were found to have a hearing loss (7).


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256 NYHAN & RICHARDSONIntracranial cc~Icifications.--Calcificafion has been observed outlining

the area of bilateral subdural membranes which had been found in a pa-tient with purulent meningitis but not removed (7). Similar calcificationshave been described in subdural hematoma (97), and may vary fromfaint strands to sheets of calcium about the lesion. Large, irregular,mottled calcifications were found in the temporoparietal region of a patientnine months after an episode of pneumococcal meningitis (98). Roentgeno-grams of the skull had been negative two weeks after the admission formeningitis. An arteriogram revealed thrombosis of the middle cerebralartery and the calcific densities were interpreted to represent an area ofencephalomalacia distal to the thrombosis. The frequency with which intra-cranial calcifications occur following pyogenic meningitis is not known.Follow-up roentgenographic examination has seldom been carried out.However, the occurrence of apparently permanent intracranial calcifica-tions, particularly in the basal meninges, is relatively common n tuber-culous meningitis (87, 99).

CO~L~CATm~S OF T~ERAPYAntibiotics.--The treatment of pyogenic meningitis represents one of

the real triumphs of antibacterial therapy; however, certain comments onantibiotic toxicity are pertinent. It has recently becomeevident (100) thatsevere, often fatal, toxic reactions may be produced in very young infantsby doses of drugs which are quite safe in older children and adults, evenwhen appropriate corrections for body size are made. Antibiotics haveprovided some of the most common and most striking examples of thisproblem. In the absence of enzymes involved in the usual detoxification ofa drug, very high blood and tissue levels result from doses usually associ-ated with safe, therapeutic levels. An example of this principle is therecently recognized toxicity of chloramphenicol in the young infant (100,101).The toxicity of the sulfonamides (100, 102, 103) and novobiocin (104)in the neonatal period are related problems. Acute toxicity studies carriedout by Michael & Sutherland (105) in newborn rats indicated that thetoxicities of ovobiocin, tetracycline, and even penicillin were higher inthe infant than in the adult. Interestingly, streptomycin was found in thesestudies to be no more toxic in the infant than in the adult. However, clini-cal toxicity to streptomycin has been described in a number of infants(100), These infants developed prolonged coma and a few deaths haveoccurred. All of these instances have resulted from inadvertent over-dosage through the use of penicillin-streptomycin combinations.

The aim of therapy in bacterial meningitis is the elimination of theinfecting organism as rapidly as possible. The use of multiple antibioticshas generally been recommended for this purpose (9), although someinvestigators have recommended the use of single agents alone (106). Onereason for the use of multiple antibiotics is to delay the emergence ofresistant strains. This approach would appear to be particularly valuable


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COMPLICATIONS OF MENINGITIS 257in the treatment of meningitis caused by H. influenzae, for resistant strainsof this organism have been found to develop in the course of strepto-mycin therapy (107). Patients with this form of meningitis are generallytreated with chloramphenicol, which has been shown to be bacteriocidalin vitro against H. influenzae (108) in concentrations readily attainablein vivo, in combination with another agent, usually sulfisoxazole. Theindications for multiple antibiotics are not so clear in meningococcalmeningitis where rapid sterilization is achievable with sulfonamides, or inpneumococcal meningitis, in which Lepper & Spies (109) found no ad-vantages in combining streptomycin with pencillin over the use of penicillinalone. Uncertainty as to the etiologic agent is probably the most commonindication for the use of multiple antibiotics. A strong case for diagnosticuncertainty was documented by Haggerty & Ziai (110), who stated thatat the Childrens Medical Center in Boston no organism was found onsmear although cultures were ultimately positive in 25 per cent of cases ofmeningitis; a wrong identification was made on smear in 10 per cent; andno organism was isolated in 15 per cent. Thus, a specific bacteriologicdiagnosis could not be made in more than 50 per cent of patients. Theseinvestigators carried out a controlled study of patients with meningitisin an attempt to answer the question of whether single or multiple drugtherapy was superior. Differences were not found between the two groups.However, the design of the study and the high incidence of initial diag-nostic uncertainty precluded a real answer to the question.Epidermoid tumors.--An association between multiple thecal puncturesand the development of intraspinal epidermoid tumors was made byChoremis and co-workers (111) with the report of a series of five patients.These cord tumors were observed three to seven years after the treatmentof tuberculous meningitis with intrathecally administered streptomycin.The absence of a stylet from the needles employed was considered to havepromoted the introduction of epithelial cells.Adrenal steroids.--An intense inflammatory reaction is one of thestriking pathologic findings in patients dying of pyogenic meningitis. Itis, therefore, not surprising that adrenal steroids have been employed.Steroid therapy has also been used in fulminant disease of the Waterhouse-Friderichsen type. This syndrome is generally associated with meningococ-cemia. However, in a recent report of 51 patients (112), only nine haddied of meningococcemia; the rest had died following septicemia whichresulted from a variety of organisms capable of producing meningitis.For these reasons, steroid therapy has been widely employed in bacterialmeningitis.

Margaretten and colleagues (112, 113) have observed venous sinusoidalthrombosis in the adrenals of patients with the Waterhouse-Friderichsensyndrome. These and other findings, including renal cortical necrosis, havesuggested a resemblance between this syndrome and the generalizedShwartzman reaction. A relationship between this complication andsteroid therapy has been raised because of the effectiveness of cortisone


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258 NYHAN & RICHARDSONin potentiating the Shwartzman reaction in experimental animals. Infact, among patients with meningococcemia studied (113), the mortalitywas higher in steroid-treated patients than in those not so treated. Thesepatients were not in shock at the time therapy was started, and there wasnothing in their records to suggest that the steroid-treated patients wereinitially more severely ill. However, this may still have been the case.Controlled data may be required to demonstrate that steroid therapy insepsis increases the likelihood of the Waterhouse-Friderichsen syndrome.Nevertheless, there seems to be little evidence of benefit from this formof therapy.

Steroid therapy in meningitis might be expected to result in any ofthe complications of steroid therapy (114), and gastrointestinal bleedinghas been observed in at least one patient (115). However, melena is seenin patients with meningitis in the absence of steroid therapy. The efficacyof hydrocortisone in the treatment of pyogenic meningitis has been studiedby Lepper & Spies (109, 116) in carefully alternated series of patients.In meningitis resulting from H. influengae, the incidence of subduraleffusions was significantly higher, not lower, in the steroid-treated group(116). This finding is consistent with observations that have been maderetrospectively (7) on the incidence of effusions in steroid-treated patients.In neither H. infl,~enzae meningitis nor in pneumococcal meningitis (109)was there any evidence of benefit from steroid therapy.

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1958)9. Alexander, H. E., Med. Clin. N. Am.,42, 575-86 (1958)10. Hare, H., Ann. Otol. Rhlnol. &Laryngol., 68, 305-14 (1959)11. Zial, M., and Haggerty, R. J., New

EngL J.Med., 259, 314-20 (1958)12. Groover, R. V., Sutherland, J. M.,and Landing, B. H., New F~ngl.I. Med., 264, 1115-21 (1961)13. Nyhan, W. L., and Fousek, M. D.,Pediatrics, 22, 268-78 (1958)14. Heilmann, E. M., Muench, Mad.Wochschr., 102, 28-31 (1960)15. Sherman, J. Ingall, D., Weiner, ~.,and Pryles, C. V., Am. f. Dis-eases Children, 100, 212-16 (1960)16. George, R. M., Cochrane, C. P., andWheeler, W. E., Am. 7. DiseasesChildren, 101, 296-304 (1961)17. Dedrick, ]., Am. J. Med. Si., 233,617-21 (1957)18. Beene, M. L., Hansen, A. E., andFulton, M., Am. Y. Diseases Chil-dren, 82, 567-73 (1951)19. Henderson, L. L., Am. J. DiseasesChildren, 75, 351-75 (1948)20. Butler, N. R., Barrie, H., and Paine,K. W. E., Arch. Disease Child-hood, 32, 461-65 (1957)21. Cabrera, H. A., and Davis, G. H.,Am. Y. Diseases Children, 101,289-95 (1961)22. Penfield, W. G., Am. 7. DiseasesChildren, 26, 383-90 (1923)


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COMPLICATIONS OF MENINGITIS 25923. Spitz, E., Pollak, A., and-Angrist,H., Arch. NeuroL Psychiat.,144-49 (1945)24. McKay, R. J., Ingraham, F. D.,Matson, D. D., and Morisette, R.A., NewEngl. .r. Med., 242, 20-21(1950)25. Ingraham, F. D., and Matson, D. D.,]. Pedlar., 24, 1-37 (1944)26. Smith, H. V., and Crothers, B.,Pediatrics, 5, 375-89 (1950)27. Arnold, G. G., .L Pediat., 84, 191-96 (1951)28. Ingraham, 17. D., and Matson, D. D.,Neurosureery of Infancy andChildhood, 186-200 (Charles

Thomas, Publ., Springfield, Ilk,1954)29. Anderson, F. M., Pediatrics, 10, 11-18 (1952)30. Williams, J. M., and Stevens, H.,I. Intern. Coil. Surgeons, 27, 590-94 (1957)31. Arnold, G. G., f. Pediat., 40, 757-60(1952)32. Gitlin, D., Pediatrics, 16, 345-52(1955)33. McKay,R. J., ~r., Ingraham, F. D.,and Matson, D. D., J. Am. Med.Assoc., 152, 387-91 (1953)34. Smith, M. H. D., Dormont, R. E.,and Prather, G. W., Pediatrics,7, 34-43 1951)35. iVIoII, . C., nd Warmington,.Pediat., 44, 41-46 (1954)36. Smith, E. S., I. Pediat., 45, 425-36(1954)37. Koch, R., and Carson, M. J., ).Pediat., 46, 18-29 (1955)38. Shaw, E. B., and Bruyn, I-I. B.,Pedlar., 56, 253-58 (1960)39. Platou, R. V., Rinker, A., and Der-rick, 2[., Pediatrics, 23, 962-71(1959)40. Smith, M. H. D., Advan. Pediat., 8,165-89 (1956)41. Streifler, M., Freundlich, E., andBelier, A. J., I. Diseases Children,95, 25-29 (1958)42. McKay, R. ]., Jr., Yearbook ofPediatrics, 371-72 (Year BookMed. Publ., Chicago, II1., 1961-1962)43. Turner, L., Lancet, I, 849-52 (1954)44. Oren, J., Schiff, G. M., Fodar, A. R.,and Mohr, D. V., Am. I. DiseasesChildren, 102, 843-52 (1961)45. Williams, J. M., and Stevens, H.,Ann. Sure., 139, 287-92 (1954)46. McKay, R. ]., It. (Personal com-munication)47. Smith, J. F., and Landing,

Neuropathol. Exptl. Neurol., 19,248-65 (1960)48. Smith, 1VL H. D., Pediatrics, 17,258-77 (1956)49. Ingraham, F. D,, and Matson, D. D.,Nenrosurgery of Infancy andChildhood, 383-85 (CharlesThomas, Publ., Springfield, Ill.,1954)50. Nyhan, W. L., and Cooke, R. E.,Pediatrics, 18, 604-13 (1956)51. Peters, J. P., Welt, L. G., Sims, E.A. H., Orloff, J., and Needham,J., Trans. Assoc. Am. Physicians,63, 57-64 (1950)52. Welt, L. G., Seldin, D. W., Nelson,W. P., III, German, W. j., andPeters, J. P., Arch. Internal Med.,90, 355-78 (1952)53. Cooke, R. E., and Ottenheimer, E.J., Advan. Pediat., 11, 81-145(1960)54. Rountree, L. G., Arch. Internal Med.,32, 157-74 (1923)55. Helwig, F. C., Schutz, C. B., andCury, D. E., ). Am. Med. Assoc.,104, 1569-75 (1935)56. Harned, Ii. S., Jr., and Cooke, R. E.,Sure. Gynecol. Obstet., 104, 43-50 (1957)57. Rapaport, S., West, C. D., andBrodsky, W. A., J. Lab. Clin.Med., 37, 550-61 (1951)58. Doxiadis, S. A., Goldfinch, M. K.,and Philpott, M. G., Brit. Med.I, 1406-10 (1954)59. Harrison, H. E., Finberg, L., andFleishman, E., d. Clin. lnvest., 31,300-81952)60. Goldherg, M., and Handier, J. S.,New Engl. J. Med., 263, 1037-43(1960)

61. Carter, N. W., Rector, F. C., Jr.,and Seldin, D. W., New Engl.Med., 264, 67-72 (1961)62. Epstein, F. H., Levitin, H., Glaser,G., and Lavietes, P., New Engl.]. Med., 265, 513-19 (1961)63. Sims, E. A. H., Welt, L. G., Orloff,J., and Needham,~. W., 1. Clin.Invest., 29, 1545-57 (1950)64. Rutstein, D. D., Thomson, K. J.,Tolmach, D. M., Walker, W. H.,and Floody, R. J., ]. Clin. Invest.,24, 11-20 (1945)65. Soule, H. C., Buckman, T. E., andDarrow, D. C., ). Clin. Invest.,5, 229-42 (1928)66. Schwartz, W. B., ]3ennett, W., Cure-lop, S., and Bartter, F. C., Am.]. Med., 23, 529-42 (1957)67. Schwartz, W. 13., Tassel, D.,


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260 NYHAN & RICHARDSONBartter, F. C., NewEngl. ]. Med.,262, 743-48 (1960)68. Schwartz, E., Fogel, R. L., Chokas,W. V., and Panariello, V. A.,Am. I. Med., 33, 39-53 (1962)69. Leaf, A., New Engl. J. Med., 267,24-30, 77-83 (1962)70. Leaf, A., Bartter, F. C., Santos, R.F., and Wrong, O., ~. Clin. In-vest., 32, 868-78 (1953)71. Spitz, E. B., Wagner, S., Sataloff,.1., I-Ioffman, N. P., and Hope, J.W., Y. Pediat., 59, 397-401 (1961)72. Tribiano, C., Y. Pediat., 42, 609-11(1953)73. Smith, C. H., Erlandson, M., Schul-man, I., and Stern, G., Am. J.Med., 22, 390-404 (1957)74. Gitlin, D., Gross, P. A. M., andJaneway, C. A., New Engl.Med., 260, 72-76 (1959)75. Fisher, D. A., Am. ]. Diseases Chil-dren, 99, 90-97 (1960)76. M6ndes-Cashion, D., and Cordero, R.,Ann. lnternal Med., 54~ 503-9(1961)77. Richardson, F. (Unpublished observa-tions)78. Dandy, W. E., Arch. Surg., 49, 75-85 (1944)79. Hoyne, A., and Schultz, A., Am. ].Med. Sci., 214, 673-76 (1947)80. B~e, J., and Huseklepp, H., Am. I.Med., 29, 465-74 (1960)81. Ross, A. T., Arch. NeuroL Psychiat.,67, 89-102 (1952)82. Bloor, B., Grant, R. S., and Tabrls,J. A., I. Am. Med. Assoc., 142,241-43 (1950)83. Bergstrand, C. G., FahMn, T., andThil6n, A., Acta Pedlar., 46, 10-17 (1957)84. Crook, W. G., Clanton, B. R., andHodes, H. L., Pediatrics, 4, 643-59 (1949)85. Wolff, O. I-I. (Personal communica-tion)86. Wolff, O. I-I., Arch. Diseases Chil-dren, 27, 302 (1952)87. Lorber, J., Pediatrics, 28, 778-91(1961) 88. Ballard, S. I., and Miller, H. G.,Lancet, II, 273-75 (1945)89. Pal, M. N., J. Mental Sci., 92, 389-410 (1946)90. Desmit, E. M., Arch. Disease Child-hood, 30, 415-18 (1955)91. Gibbs, F. A., Gibbs, E. L., Carpenter,E. R., and Spies, H. W., Pediat-rics, 29, 181-86 (1962)92. Cargill, W. H., and Beeson, P. B.,

Ann. Internal Med., 27, 396-400(1947)93. Richardson, F., and Battaglia, F.,Pediatrics (In press)94. Kinney, C., Arch. OtolaryngoL, 47,303-9 (1948)95. Richardson, F., Proc. Intern. Congr.Pediat. 10th Congr. (In press)96. Barton, M. E., Court, S. D., andWalker, W., Brit. Med. Y., I~ 351-55 (1962)97. Camp, jr. D., ]. Am. Med. Assoc.,137~ 1023-31 (1948)98. Levinson, A., and Hartenstein, H.,]. Pedlar., 38~ 624-29 (1951)99. Lincoln, E. M., Sordillo, S. V. R.,and Davies, P. A., Y. Pedlar., 57~807-23 (1960)100. Nyhan, W. L., I. Pediat., 59, 1-20(1961)101. Weiss, C. F., Glazko, A. J., andWeston, jr. K., NewEngl. ]. Med.,262, 787-94 (1960)102. Silverman, W. A., Andersen, D. H.,Blanc, W. A., and Crozier, D. N.,Pediatrics, 18, 514-25 (1956)103. Odell, G. B., ]. Clin. Invest., 38,823-33 (1959)104. Sutherland, jr. M., and Keller, W.H., ]. Diseases Children, 101, 447-53 (1961)105. Michael, A. F., and Sutherland, J.M., ]. Diseases Children, 101~442-46 (1961)106. Pryles, C. V., Pediatrics, 21~ 1000-9 (1958)107. Alexander, I-I. E., Am. $. Med., 2~457-66 (1947)108. Alexander, H. E., Leidy, G., andRedman, W., ]. Clin. Invest., 28,867-70 (1949)109. Lepper, M. H., and Spies, H. W.,Arch. Internal Med., 104, 253-59(1959)110. Haggerty, R. J., and Zial, M., Pediat-rics, 25~ 742-47 (1960)111. Choremis, C., Economos, D., Papa-datos, C., and Gargonlas, A., Lan-cet, II, 437-39 (1956)112. Margaretten, W., Nakai, H., andLanding, B. trI., Proc. Soc. Pedlar.Res., 32, 8 (1962)113. Margaretten, W., and McAdams, A.jr., An*. J. Med., 25, 868-76 (1958)114. Good, R. H., Vernier, R. L., andSmith, R. T., Pediatrics, I9, 95-118 (1957)115. Holdsworth, D. E., Arch. InternalMed., I06~ 653-56 (1960)116. Lepper, M. H., and Spies, H. W.,Antibiot. Ann., 336-49 (1958)


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