CLINICAL REVIEW
Brain Abscess: A Review of Recent Experience NELSON S. BREWER, M.D., COLLIN S. MacCARTY, M.D., and WILLIAM E. WELLMAN, M.D., Rochester, Minnesota
From 1961 through 1973, 60 patients with brain abscess were treated at the Mayo Clinic by surgical excision and antimicrobial therapy. The operative mortality was 1 7 % , which was identical to a similar series reported in 1959. The patients who had the diagnosis of brain abscess confirmed at autopsy and who never underwent operation (24 patients) were more elderly than the group operated on, and a higher percentage had multiple brain abscess. Severe systemic disease or multisystem disease, or both, usually precluded a vigorous surgical approach among the nonsurgical group. Etiologic, diagnostic, and microbiologic factors were examined to develop an approach to antimicrobial therapy.
group did not include any patients in whom abscesses in multiple organs indicated that the brain involvement was merely a part of a generalized terminal septic process. Excluded from the study were patients who were considered to have a focal cerebritis and whose condition improved with antimicrobial therapy alone. SURGICAL PROCEDURES
Well-encapsulated abscesses, together with the abscess walls, were excised when operative conditions permitted. When excision of the intact lesion was not possible, the abscess was evacuated and the cavity debrided. A solution consisting of penicillin G (1000 U/ml) and crystalline streptomycin (5 mg/ ml) was used to irrigate the cavity. MICROBIOLOGIC TECHNIQUES
I N 1959, a review of the cases of brain abscess treated surgically at the Mayo Clinic from 1946 through 1955 showed that there had been 60 such cases, with 10 deaths (mortality, 17%) ( 1 ) . From 1961 through 1973, another 60 patients were operated on for brain abscess, and the mortality for this group was identical to that of the previous group. Although this mortality compares favorably with that of other operative series, in which the mortality ranged from 18% to 50% (2-7), the lack of improvement in the outcome of treatment for brain abscess from 1959 to 1973 is disconcerting. This absence of a further diminution in mortality since the advent of penicillin was the subject of a recent editorial ( 8 ) . The overall mortality (surgical and nonsurgical cases) for this disease ranges from 36% to 65% (2-7, 9 ) . We analyzed the records of the 60 patients with brain abscess in whom the diagnosis was made at operation (surgical group) and of 24 patients in whom the diagnosis was made only at autopsy (nonsurgical group) from 1961 through 1973. In particular, we examined etiologic, microbiologic, and therapeutic factors in order to develop a rational approach to the management of brain abscess. Patients and Methods
The 60 patients in this series who were operated on all had documented evidence of intracerebral abscess; patients with subdural and epidural empyemas were excluded. The autopsy • From the Mayo Clinic and Mayo Foundation, Rochester, Minnesota.
Before 1968, abscess material was cultured using the following media: calf-brain broth, phenylethyl alcohol agar, Levin's eosin methylene blue agar, and human blood agar. Streptococci that required the presence of carbon dioxide for growth on primary isolation on agar plates were termed "microaerophilic." Since 1968, abscess material has been cultured according to standard procedures described elsewhere (10). Those organisms classified as microaerophilic before 1968 were placed in the Streptococcus viridans group thereafter, because all primary cultures of purulent material are incubated in 10% C0 2 . The viridans streptococci do not represent a single species; rather, they constitute a heterogeneous group composed of various streptococci that could not otherwise be grouped. Special cultures for anaerobic organisms were also made (10). Since mid-1970, a glass tube with a butyl rubber stopper, flushed with oxygen-free C0 2 , has been available for the collection of anaerobic specimens for culture. Since 1971, the differentiation of anaerobic organisms has been based on the use of gas-liquid chromatography and other methods (11). Results SURGICAL GROUP
Age and Sex Distribution: The ages of the patients by decade are shown in Table 1. There were 37 men and 23 women. Etiologic Factors: The predisposing factors or primary focuses of infection that could be determined with confidence are presented in Table 2. One patient was operated on for brain abscess at the Mayo Clinic after 2 weeks of therapy elsewhere for purulent meningitis. Mortality and Morbidity: Patients were considered to have disabling neurologic sequels when they were unable to work or resume activity similar to that before the development of the abscess (Table 3 ) . In at least 5 patients,
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whom these organisms were isolated died. Six of the eight patients from whom staphylococci were isolated had a history of recent penetrating head trauma or craniotomy. More than one organism were recovered from the abscesses of 19 patients. Anaerobic organisms were recovered from 2 1 % of the patients through 1970; since then, however, this proportion has increased to 5 0 % . The recovery of multiple organisms has increased from 25% of the patients through 1970 to 5 8 % of the patients after 1970. Bacteroides species were isolated in only 4 patients. None of these organisms, however, was identified as B. fragilis, although two of the isolates before 1968 were not speciated. The distribution of organisms isolated from the brain abscesses of patients, with each suspected etiologic focus of infection, is summarized in Table 5. All of the patients from whom a member of the family Enterobacteriaceae was cultured had a chronic infection of the sinus or ears, except for one patient in whom the abscess developed subsequent to a skull fracture. The two patients from whom H. influenzae was isolated were 16 and 30 years old. Diagnostic Studies: Confirmation of the diagnosis was made by various studies (Table 6 ) . Two of the three patients in whom the arteriogram failed to localize a lesion had multiple abscesses. Treatment: As a major part of the therapy, penicillin G was given to 46 patients and either ampicillin or a penicillinase-resistant penicillin to 8 other patients. Cephalothin was given as the major part of therapy to three patients who were allergic to penicillin. Chloramphenicol was given for more than 7 days to 23 patients, 2 ( 9 % ) of whom died. Three of the 4 patients from whom Bacteroides species were isolated received chloramphenicol in addition to other antibiotics, and the fourth received tetracycline. Antibiotic therapy for 14 to 25 days after operation was part of the management of 25 patients, 3 (12%) of whom died; antibiotics were given for longer than 25 days after operation to 21 patients, 2 (9.5%) of whom died. One patient with a ruptured brain abscess associated with Escherichia coli was cured without residual neurologic damage after receiving gentamicin given parenterally for 60 days, as well as 10 doses given intrathecally. The two patients with Enterobacter organisms isolated from the abscesses were successfully treated without intrathecal antibiotics; one received gentamicin parenterally and the other received kanamycin parenterally. Five abscesses recurred; all resolved with retreatment. One patient, from whose abscess S. viridans and Corynebacterium species were cultured, required reoperation while receiving penicillin G and chloramphenicol 12 days after the initial operation. Two other patients required reoperation 1 month after the initial procedure; one patient had received an antibiotic for 9 days and the other for 16 days after the initial procedure. The remaining two patients required reoperation more than 2 years after the initial procedure, but in each an adjacent focus of infection persisted.
Table 1. Age by Decade of Patients in Surgical and Autopsy Groups
Decade of Life
Surviving
yrs 0-9 10-19 20-29 30-39 40-49 50-59 60-69 70-79 Total
Autopsy Group (#i = 24)
Surgical Group (n = 60) Not Surviving
>
(
6 10 6 5 5 9 7 2 50
3 3 2 1 2 5 4 4 24
1 1 0 1 3 1 3 0 10
the residual neurologic damage was considered to have resulted from the predisposing condition rather than the abscess itself. Multiple brain abscesses developed in 8 patients. Five of these patients died (mortality, 6 2 % ) , 2 recovered completely, and 1, whose lesions were caused by a gunshot wound to the head, was left with severe neurologic impairment. In the other 52 patients, the brain abscesses were solitary. Among these patients, 5 died (mortality, 1 0 % ) . Organisms Isolated: Table 4 lists the organisms isolated from the abscesses. Operative cultures yielded negative growths in 13 cases. Streptococci were isolated in 32 instances. Of the 32 species, 10 were anaerobic streptococci. Among the ten patients from whom anaerobic streptococci were recovered, four died, and four were left with disabling residual neurologic damage. Three of the four patients who died with anaerobic streptococcal abscesses had multiple abscesses, and the fourth had a large multiloculated abscess. At least 1 additional organism was recovered from eight of the ten patients with anaerobic streptococci. Various organisms were recovered in association with the anaerobic streptococci, and no single organism was found to be associated in more than 2 instances. Of the 18 isolates of Streptococcus viridans, 5 were originally designated as microaerophilic streptococci; none of the five patients from Table 2. Suspected Etiologic Factor in Patient:s with Brain / Vbscesses in Surgical Group Etiologic Factor
Patients
Deaths nc
Otic or cellulitis paranasalafter sinuseyeinfection Orbital surgery Abdominal infection (cholecystectomy, diverticulitis) Pulmonary infection Endocarditis Congenital heart disease Dental procedure or abscess Trauma Head injury Surgery Postmeningitic status Unknown Total 572
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12 1
1 0
2 8 1 5 4
1 3 0 2 0
5 6 1 15 60
0 0 0 3 10
• Annals of Internal Medicine • Volume 82 • Number
AUTOPSY GROUP
Age and Sex Distribution: The ages of the patients by decade are shown in Table 1. There were 16 men and 8 4
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Table 3. Morbidity and Mortality in Surgical Group
Outcome Death Cure with minimal or no residual damage Residual neurologic disability Total
Patients no. 10 31 19* 60
% 17 52 31 100
* Includes 5 with damage attributed to underlying condition: tumor, 1; trauma, 2; and postoperative status, 2.
women. Clinical and Bacteriologic Data: Of these 24 patients, 15 ( 6 2 % ) presented with purulent meningitis. In 9 of the 15 patients, the abscess was shown at autopsy to have ruptured into the ventricular system and resulted in meningitis. Five patients had associated endocarditis. In 2 of them, the endocarditis developed within hours of prosthetic valve replacement; these patients remained comatose until death. Another patient was admitted in severe heart failure and died 1 day later. In a fourth patient, the brain abscess appeared to progress while the patient was receiving therapy for endocarditis. This patient, who had focal neurologic signs on admission 35 days before death, received penicillin and streptomycin therapy for the endocarditis associated with infection by Streptococcus mitis. He became irrational and disoriented 12 days before death. An arteriogram performed 3 days before death did not show the left frontal lobe abscess. (Arteriograms failed to show a mass lesion in another
2 patients.) Multiple abscesses were found in 3 of the 5 patients with endocarditis. In 2 patients, Nocardia asteroides was recovered; in each patient, the abscesses were multiple. Of the 24 patients constituting the autopsy group, 9 ( 3 8 % ) had multiple abscesses. Five of the 24 patients had carcinoma, and, in most instances, the cerebral lesion was thought to be metastatic tumor. In 2 infants with congenital abnormalities, cerebral abscesses developed after overwhelming pneumonia. The details of 1 of the 24 patients whose abscess grew Corymebacterium hemolyticum have been reported by Washington, Martin, and Spiekerman (12). Discussion AGE AND SEX
Brain abscesses can occur at all ages of life. Our data show peak incidences in the first 2 decades of life and in the 2 decades between 50 and 70 years of age. Of the patients in the autopsy group, 3 3 % were older than 60 years, as were 20% of those in the surgical group. The men:women ratio in both groups combined was almost 2 : 1 ; this prevalence among men has been noted by others (3,4,6,13). CLINICAL PRESENTATION
Brain abscesses frequently present as expanding intracranial lesions, with headache and focal neurologic signs (3, 6, 7, 14), rather than as infectious processes. Fever is frequently absent (2, 3, 6, 7, 15).
Table 4. Organisms Isolated from Surgical Group
Organism
Isolates
As Part of Mixed Infection
As Single Isolate
Deaths
Major Neurologic Residual
— no. Aerobic organisms Streptococcus viridans Streptococcus pneumoniae Streptococcus group A Streptococcus group F Staphylococcus aureus Staphylococcus epidermidis Corynebacterium species Escherichia coli Enterobacter cloacae Enterobacter aerogenes Proteus species Hemophilus influenzae Hemophilus parainfluenzae Hemophilus aphrophilus Acinetobacter calcoaceticus Pseudomonas maltophilia Unclassified Gram-negative bacilli Actinobacillus actinomycetemcomitans Anaerobic organisms Peptostreptococcus Propionibacterium acnes Bacteroides species Bade wide s meIan ino genieus Bacteroides pneumosintes Eubacterium lentum Fusob acterium fusiforme Actinomyces israelii
18 1 2 1 7 1 3 1 1 1 1 2 2 2 2 1 3 2
7 0 0 1 1 1 3 0 1 0 0 2 1 2 2 1 3 1
11 1 2 0 6 0 0 1 0 1 1 0 1 0 0 0 0 1
3 0 0 0 0 1 0 0 0 0 1 0 0 1 0 0 0 1
4 0 1 0 3 0 1 0 0 0 0 0 1 0 0 1 1 1
10 5 2 1 1 1 1 1
8 5 2 1 1 1 1 0
2 0 0 0 0 0 0 1
4 1 0 0 0 0 0 1
4 0 1 0 0 0 0 0
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Table 5. Organisms Isolated from Brain Abscesses of Surgical Patients with Various Etiologic Infective Factors
Suspected Etiologic Factor
Organism Recovered
Otic or paranasal sinus infection
Streptococcus viridans, Streptococcus group A, Streptococcus pneumoniae, Staphylococcus aureus, Hemophilus aphrophilus, Enterobacter cloacae, Enterobacter aerogenes, Proteus species, Propionibacterium acnes, Peptostreptococcus, Eubacterium lentum, Bacteroides pneumosintes Streptococcus viridans, Streptococcus group F, Hemophilus parainfluenzae, Corynebacterium species, Peptostreptococcus, Propionibacterium acnes, Bacteroides species Streptococcus viridans, Pseudomonas maltophilia, Actinobacillus actinomycetemcomitans, Propionibacterium acnes, Peptostreptococcus, Actinomyces israelii, Bacteroides species Streptococcus group A, Staphylococcus aureus, Staphylococcus epidermidis, Hemophilus influenzae, Escherichia coli, Acinetobacter calcoaceticus, Peptostreptococcus, Bacteroides melan inogenie us Streptococcus viridans, Hemophilus parainfluenzae, Hemophilus aphrophilus, Propionibacterium acnes, Peptostreptococcus
Oral infection Pulmonary infection Head trauma or surgery
Congenital heart disease
bacillus actinomycetemcomitans, which is frequently found in lesions in association with A. israelii (21), was found in the brain abscesses of two patients, neither of whom, however, was found to have actinomycosis. Six of the eight staphylococcal isolates were recovered from the brain abscesses of patients who had sustained head trauma or who had had an operation. However, various other organisms were found in brain abscesses after head trauma or surgery (Table 5 ) ; as this table shows, Gram-negative aerobic and anaerobic organisms were recovered from patients with a variety of etiologic focuses of infection. These findings indicate that, despite knowledge of the underlying focus of infection, various organisms may be etiologic agents in brain abscesses. Furthermore, more than one organism was isolated from the brain abscesses of 32% of the patients in the surgical group. Therefore, the initial antibiotic program must cover a broad spectrum of organisms. Gram's stains of purulent material draining from the brain abscess recovered at operation, as well as information about organisms cultured from other focuses of infection, are helpful in planning the initial antibiotic regimen. However, empirical antibiotic therapy is indicated.
In general, the clinical presentation was more fulminating in the autopsy group of patients than in those of the surgical group. Severe neurologic disease or multisystem disease, or both, usually precluded a vigorous surgical approach. Five (21%) patients in the autopsy group had endocarditis. In at least one of them, the abscess appeared to progress, although the patient was receiving appropriate antibiotic therapy for endocarditis. Neurologic complications are not uncommon in patients with endocarditis (16), and endocarditis must be suspected in any instance of purulent infection of the central nervous system when the cause is not otherwise obvious. Patients being treated for endocarditis likewise should be observed closely during and immediately after treatment for the possible development of a neurologic lesion. The one patient in the surgical group who had endocarditis showed focal neurologic signs on the day after withdrawal of penicillin and streptomycin therapy for endocarditis due to infection with S. viridans. The two patients in the autopsy group who had infection with N. asteroides had obvious pulmonary involvement. Survival is notoriously poor with cerebral nocardiosis (reported mortality, 8 7 % ) (17). Recovery of this organism from any source in a patient with immunologic impairment or in patients with clinical evidence of infection calls for vigorous antimicrobial therapy. Appropriate therapy should be instituted according to the susceptibility of the organism in vitro, and the patient should be observed closely for evidence of central nervous system involvement (18).
THERAPEUTIC APPROACH TO BRAIN ABSCESS
Clinical findings and brain scanning may indicate early infective brain lesions in the stage of cerebritis ( 2 2 ) . Prompt diagnosis and vigorous antimicrobial therapy in the early stages of cerebritis may prevent abscess formation (23). However, because relapses requiring surgical intervention following medical therapy alone have been reported (23), patients treated expectantly by medical therapy alone must be observed closely for signs of deterioration or relapse. Black, Graybill, and Characbi (24) demonstrated viable organisms in brain abscesses despite therapeutically effective antibiotic concentrations in the abscesses. In our series, a brain abscess appeared to have progressed during appropriate therapy for endocarditis in one patient in the surgical group and in one patient in the autopsy group. Thus, surgical evacuation of brain abscesses is essential; antibiotic therapy alone is not sufficient. We believe that all brain abscesses should be treated surgically when they are diagnosed. Patients with cerebritis not responding to antimicrobial therapy undergo opera-
ASSOCIATED INFECTIONS AND ORGANISMS ISOLATED
A primary focus of infection could not be determined with confidence in 25% of the patients in the surgical group. Among those with another identifiable focus of infection, various microorganisms were recovered from the brain abscesses, regardless of the etiologic focus of infection (Table 5 ) . We noted, as have others (19), that brain abscesses not resulting from intracranial surgery or trauma frequently follow metastatic spread of infection from a focus of chronic suppuration. Hematogenous dissemination of Actinomyces israelii is a rare complication of actinomycosis (20, 2 1 ) . Actino574
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• Annals of Internal Medicine • Volume 82 • Number
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tion when signs of clinical deterioration appear. Abscesses involving vital brain centers are explored when the abscess appears to be threatening the life of the patient. When the etiologic focus of infection is in the mouth, ears, paranasal sinuses, lungs, or abdomen, or when the focus is indeterminate, a reasonable antibiotic regimen would consist of the administration of penicillin G, chloramphenicol, and gentamicin. We usually give these antibiotics, on a daily basis, as follows: penicillin G, 20 million units by intravenous infusion; chloramphenicol, 50 to 100 mg/kg body weight intravenously; and gentamicin, 5 to 6 mg/kg body weight either intramuscularly or intravenously. These doses are, of course, altered depending on associated disease or renal impairment. Streptococci are the most frequently isolated organisms from brain abscesses, and all except the enterococci are susceptible to penicillin G. Penicillin should be used in addition to chloramphenicol, because penicillin G is a bactericidal antibiotic, whereas chloramphenicol is not (25). The possibility of antimicrobial antagonism exists with the combination of penicillin G and chloramphenicol, but this is not a problem as long as penicillin therapy is started before or at the time of chloramphenicol (26). N o enterococci were isolated from the present series of patients; however, these organisms have been reported in cases of brain abscess ( 4 ) . Enterococcal infections usually require the synergistic action of penicillin plus an aminoglycoside to kill the organism (27). Bacteroides fragilis has been isolated previously from brain abscesses ( 1 9 ) , and, although no B. fragilis was identified in the present series, two of the Bacteroides isolates were not speciated. Bacteroides fragilis is usually resistant to penicillin and the aminoglycosides; however, chloramphenicol is an effective agent for this organism (28). Administration of both penicillin G and chloramphenicol—especially the latter— has been shown to produce effective concentrations in brain tissue (29). With gentamicin, there are no reliable studies, of which we are aware, that concern its concentration in brain tissue. The importance of the production of therapeutic levels of an antibiotic in the cerebrospinal fluid in the treatment of brain abscess is unknown. Penicillin G does not penetrate well into the cerebrospinal fluid in the absence of meningitis; however, this difficulty can be overcome by giving very high doses of this relatively nontoxic antibiotic (30). Chloramphenicol reaches a concentration in the cerebrospinal fluid that is 3 0 % to 5 0 % of the plasma concentration, even in the absence of meningeal inflammation (30). Gentamicin does not penetrate into the cerebrospinal fluid readily, and it has been recommended that, when this agent is used for the treatment of meningitis due to Gram-negative organisms, administration should be intrathecal as well as intravenous ( 3 1 ) . Because Gram-negative aerobic organisms have been isolated from brain abscesses in patients who have otic, paranasal sinus, or pulmonary infection, who have a history of complicating head trauma, or who have had an operation recently, gentamicin should be given until a microbiologic report is available. Both gentamicin (32)
Table 6. Diagnostic Procedures in Surgical Group
Procedure
Brain scan Computerized axial tomography Echoencephalogram Electroencephalogram Arteriogram Ventriculogram Pneumoencephalogram
Patients
Procedures with Abnormal Result
no.
no. (%)
8 1 18 37 47 8 4
8(100) 1 (100) 5(28) 33 (90) 44 (94) 8(100) 4(100)
and chloramphenicol (33,*) have antistaphylococcal activity that might be of value in unsuspected cases of infection with a penicillin-resistant staphylococcus. If an adjacent staphylococcal focus of infection is present, or if the brain abscess has developed after intracranial surgery or trauma, a penicillinase-resistant penicillin, such as oxacillin or methicillin, should be substituted for penicillin G in the triple-drug regimen. The initial antibiotic regimen should, of course, be altered when microbiologic data, including susceptibility studies, become available. The condition of two patients relapsed after they had received antibiotics postoperatively for 9 and 16 days. Except for one patient, no patient had a relapse after receiving antimicrobial therapy after operation for longer than 4 weeks; the one exception had a persistent otitis due to infection with S. aureus and had a recurrence, or reinfection, 4 years after the completion of a 31-day course of parenteral antimicrobial therapy. In view of Braude's (19) experience with two patients who had relapses after 2 and 3 weeks of antibiotic therapy, it seems reasonable to continue antimicrobial therapy for at least 4 weeks after operation to prevent relapse. DIAGNOSTIC STUDIES
Lumbar puncture in patients with possible brain abscesses should be discouraged. Frequently, only minimal information is obtained (2, 15, 19); the lethal complication of brain herniation has been repeatedly emphasized (2, 9, 15, 3 4 ) . Our data show that patients with brain abscesses not uncommonly present with purulent meningitis. If the history suggests the possibility of a ruptured brain abscess, the noninvasive technique of computerized axial tomography might rapidly demonstrate and localize the lesion. In our series, as well as those of others ( 3 , 14, 22, 35), brain scanning was both sensitive and accurate in showing these lesions. However, lesions less than 1 cm in diameter may not be seen by scanning, especially if these lesions are multiple ( 3 5 ) . Electroencephalography was more useful in our patients than has been reported by others (2, 9, 14). Arteriography, although reliable in this series and in others ( 3 ) , also may be misleading ( 3 6 ) . Computerized axial tomography with an E M I scannert was used in one case and accurately showed the lesion. This method may well become more important in the diagnosis and follow-up of patients with brain abscess. * SECTION OF CLINICAL MICROBIOLOGY, MAYO CLINIC: Unpublished data.
t EMI Limited, London, England. Brewer et a/. • Brain Abscess
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ADDITIONAL FACTORS INFLUENCING PROGNOSIS
Sperl, MacCarty, and Wellman (1) reported a higher mortality among patients with streptococcal infection. The striking mortality and morbidity in our surgical group were among those patients from whom anaerobic streptococci were isolated (Table 4 ) . These patients were affected by various predisposing factors and organisms. There is a possibility that anaerobic streptococci are particularly destructive to brain tissue. Liske and Weikers (4) also reported a particularly high mortality among patients with brain abscesses from which anaerobic streptococci were isolated. A high mortality among patients with multiple brain abscesses has been the experience of others ( 2 ) . In our series, 37% of the autopsy group as opposed to 13% of the surgical group had multiple brain abscesses. The eight patients with multiple brain abscesses in the surgical group accounted for 5 of the 10 surgical deaths. The recovery and identification of microorganisms— especially anaerobic organisms—from brain abscesses at the Mayo Clinic have improved since 1970. Improved recovery of anaerobic and fastidious organisms can best be attributed to more effective transport of specimens and more effective isolation procedures. It is to be hoped that in the future more accurate microbiologic data will lead to greater effectiveness of antimicrobial therapy and a decrease in operative mortality, which has not changed since 1959.
cedures in Clinical Microbiology, edited by WASHINGTON J A I I . Boston, Little, Brown & Company, 1974, p . 15 11. T H E ANAEROBE LABORATORY: Outline of Clinical Methods in Anaerobic Bacteriology. Blacksburg, Virginia Polytechnic Institute, 1970 12.
with Corynebacterium hemolyticum: report of a case. Am J Clin Pathol 56:212-215, 1971 13. KISER J L , KENDIG J H : Intracranial suppuration: a review of 139 consecutive cases with electro-microscopic observations o n three. J Neurosurg 20:494-511, 1963 14.
• Requests for reprints should b e addressed t o Nelson S. Brewer, M . D . , c / o Section of Publications, M a y o Clinic, Rochester, M N 55901.
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residua in patients surviving brain abscess with surgery. / Neurosurg 34:652-656, 1971 35. DAVIS D O , POTCHEN E J : Brain scanning a n d intracranial inflammatory disease. Radiology 95:345-346, 1970 36. BLIGH A S , RACK P M H : Carotid angiography a n d cerebral a b scess. / Neurosurg 19:483-486, 1962
April 1975 • Annals of Internal Medicine • Volume 82 • Number 4
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Brain Abscess: A Review of Recent Experience NELSON S. BREWER, M.D., COLLIN S. MacCARTY, M.D., and WILLIAM E. WELLMAN, M.D., Rochester, Minnesota
From 1961 through 1973, 60 patients with brain abscess were treated at the Mayo Clinic by surgical excision and antimicrobial therapy. The operative mortality was 1 7 % , which was identical to a similar series reported in 1959. The patients who had the diagnosis of brain abscess confirmed at autopsy and who never underwent operation (24 patients) were more elderly than the group operated on, and a higher percentage had multiple brain abscess. Severe systemic disease or multisystem disease, or both, usually precluded a vigorous surgical approach among the nonsurgical group. Etiologic, diagnostic, and microbiologic factors were examined to develop an approach to antimicrobial therapy.
group did not include any patients in whom abscesses in multiple organs indicated that the brain involvement was merely a part of a generalized terminal septic process. Excluded from the study were patients who were considered to have a focal cerebritis and whose condition improved with antimicrobial therapy alone. SURGICAL PROCEDURES
Well-encapsulated abscesses, together with the abscess walls, were excised when operative conditions permitted. When excision of the intact lesion was not possible, the abscess was evacuated and the cavity debrided. A solution consisting of penicillin G (1000 U/ml) and crystalline streptomycin (5 mg/ ml) was used to irrigate the cavity. MICROBIOLOGIC TECHNIQUES
I N 1959, a review of the cases of brain abscess treated surgically at the Mayo Clinic from 1946 through 1955 showed that there had been 60 such cases, with 10 deaths (mortality, 17%) ( 1 ) . From 1961 through 1973, another 60 patients were operated on for brain abscess, and the mortality for this group was identical to that of the previous group. Although this mortality compares favorably with that of other operative series, in which the mortality ranged from 18% to 50% (2-7), the lack of improvement in the outcome of treatment for brain abscess from 1959 to 1973 is disconcerting. This absence of a further diminution in mortality since the advent of penicillin was the subject of a recent editorial ( 8 ) . The overall mortality (surgical and nonsurgical cases) for this disease ranges from 36% to 65% (2-7, 9 ) . We analyzed the records of the 60 patients with brain abscess in whom the diagnosis was made at operation (surgical group) and of 24 patients in whom the diagnosis was made only at autopsy (nonsurgical group) from 1961 through 1973. In particular, we examined etiologic, microbiologic, and therapeutic factors in order to develop a rational approach to the management of brain abscess. Patients and Methods
The 60 patients in this series who were operated on all had documented evidence of intracerebral abscess; patients with subdural and epidural empyemas were excluded. The autopsy • From the Mayo Clinic and Mayo Foundation, Rochester, Minnesota.
Before 1968, abscess material was cultured using the following media: calf-brain broth, phenylethyl alcohol agar, Levin's eosin methylene blue agar, and human blood agar. Streptococci that required the presence of carbon dioxide for growth on primary isolation on agar plates were termed "microaerophilic." Since 1968, abscess material has been cultured according to standard procedures described elsewhere (10). Those organisms classified as microaerophilic before 1968 were placed in the Streptococcus viridans group thereafter, because all primary cultures of purulent material are incubated in 10% C0 2 . The viridans streptococci do not represent a single species; rather, they constitute a heterogeneous group composed of various streptococci that could not otherwise be grouped. Special cultures for anaerobic organisms were also made (10). Since mid-1970, a glass tube with a butyl rubber stopper, flushed with oxygen-free C0 2 , has been available for the collection of anaerobic specimens for culture. Since 1971, the differentiation of anaerobic organisms has been based on the use of gas-liquid chromatography and other methods (11). Results SURGICAL GROUP
Age and Sex Distribution: The ages of the patients by decade are shown in Table 1. There were 37 men and 23 women. Etiologic Factors: The predisposing factors or primary focuses of infection that could be determined with confidence are presented in Table 2. One patient was operated on for brain abscess at the Mayo Clinic after 2 weeks of therapy elsewhere for purulent meningitis. Mortality and Morbidity: Patients were considered to have disabling neurologic sequels when they were unable to work or resume activity similar to that before the development of the abscess (Table 3 ) . In at least 5 patients,
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whom these organisms were isolated died. Six of the eight patients from whom staphylococci were isolated had a history of recent penetrating head trauma or craniotomy. More than one organism were recovered from the abscesses of 19 patients. Anaerobic organisms were recovered from 2 1 % of the patients through 1970; since then, however, this proportion has increased to 5 0 % . The recovery of multiple organisms has increased from 25% of the patients through 1970 to 5 8 % of the patients after 1970. Bacteroides species were isolated in only 4 patients. None of these organisms, however, was identified as B. fragilis, although two of the isolates before 1968 were not speciated. The distribution of organisms isolated from the brain abscesses of patients, with each suspected etiologic focus of infection, is summarized in Table 5. All of the patients from whom a member of the family Enterobacteriaceae was cultured had a chronic infection of the sinus or ears, except for one patient in whom the abscess developed subsequent to a skull fracture. The two patients from whom H. influenzae was isolated were 16 and 30 years old. Diagnostic Studies: Confirmation of the diagnosis was made by various studies (Table 6 ) . Two of the three patients in whom the arteriogram failed to localize a lesion had multiple abscesses. Treatment: As a major part of the therapy, penicillin G was given to 46 patients and either ampicillin or a penicillinase-resistant penicillin to 8 other patients. Cephalothin was given as the major part of therapy to three patients who were allergic to penicillin. Chloramphenicol was given for more than 7 days to 23 patients, 2 ( 9 % ) of whom died. Three of the 4 patients from whom Bacteroides species were isolated received chloramphenicol in addition to other antibiotics, and the fourth received tetracycline. Antibiotic therapy for 14 to 25 days after operation was part of the management of 25 patients, 3 (12%) of whom died; antibiotics were given for longer than 25 days after operation to 21 patients, 2 (9.5%) of whom died. One patient with a ruptured brain abscess associated with Escherichia coli was cured without residual neurologic damage after receiving gentamicin given parenterally for 60 days, as well as 10 doses given intrathecally. The two patients with Enterobacter organisms isolated from the abscesses were successfully treated without intrathecal antibiotics; one received gentamicin parenterally and the other received kanamycin parenterally. Five abscesses recurred; all resolved with retreatment. One patient, from whose abscess S. viridans and Corynebacterium species were cultured, required reoperation while receiving penicillin G and chloramphenicol 12 days after the initial operation. Two other patients required reoperation 1 month after the initial procedure; one patient had received an antibiotic for 9 days and the other for 16 days after the initial procedure. The remaining two patients required reoperation more than 2 years after the initial procedure, but in each an adjacent focus of infection persisted.
Table 1. Age by Decade of Patients in Surgical and Autopsy Groups
Decade of Life
Surviving
yrs 0-9 10-19 20-29 30-39 40-49 50-59 60-69 70-79 Total
Autopsy Group (#i = 24)
Surgical Group (n = 60) Not Surviving
>
(
6 10 6 5 5 9 7 2 50
3 3 2 1 2 5 4 4 24
1 1 0 1 3 1 3 0 10
the residual neurologic damage was considered to have resulted from the predisposing condition rather than the abscess itself. Multiple brain abscesses developed in 8 patients. Five of these patients died (mortality, 6 2 % ) , 2 recovered completely, and 1, whose lesions were caused by a gunshot wound to the head, was left with severe neurologic impairment. In the other 52 patients, the brain abscesses were solitary. Among these patients, 5 died (mortality, 1 0 % ) . Organisms Isolated: Table 4 lists the organisms isolated from the abscesses. Operative cultures yielded negative growths in 13 cases. Streptococci were isolated in 32 instances. Of the 32 species, 10 were anaerobic streptococci. Among the ten patients from whom anaerobic streptococci were recovered, four died, and four were left with disabling residual neurologic damage. Three of the four patients who died with anaerobic streptococcal abscesses had multiple abscesses, and the fourth had a large multiloculated abscess. At least 1 additional organism was recovered from eight of the ten patients with anaerobic streptococci. Various organisms were recovered in association with the anaerobic streptococci, and no single organism was found to be associated in more than 2 instances. Of the 18 isolates of Streptococcus viridans, 5 were originally designated as microaerophilic streptococci; none of the five patients from Table 2. Suspected Etiologic Factor in Patient:s with Brain / Vbscesses in Surgical Group Etiologic Factor
Patients
Deaths nc
Otic or cellulitis paranasalafter sinuseyeinfection Orbital surgery Abdominal infection (cholecystectomy, diverticulitis) Pulmonary infection Endocarditis Congenital heart disease Dental procedure or abscess Trauma Head injury Surgery Postmeningitic status Unknown Total 572
April 1975
12 1
1 0
2 8 1 5 4
1 3 0 2 0
5 6 1 15 60
0 0 0 3 10
• Annals of Internal Medicine • Volume 82 • Number
AUTOPSY GROUP
Age and Sex Distribution: The ages of the patients by decade are shown in Table 1. There were 16 men and 8 4
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Table 3. Morbidity and Mortality in Surgical Group
Outcome Death Cure with minimal or no residual damage Residual neurologic disability Total
Patients no. 10 31 19* 60
% 17 52 31 100
* Includes 5 with damage attributed to underlying condition: tumor, 1; trauma, 2; and postoperative status, 2.
women. Clinical and Bacteriologic Data: Of these 24 patients, 15 ( 6 2 % ) presented with purulent meningitis. In 9 of the 15 patients, the abscess was shown at autopsy to have ruptured into the ventricular system and resulted in meningitis. Five patients had associated endocarditis. In 2 of them, the endocarditis developed within hours of prosthetic valve replacement; these patients remained comatose until death. Another patient was admitted in severe heart failure and died 1 day later. In a fourth patient, the brain abscess appeared to progress while the patient was receiving therapy for endocarditis. This patient, who had focal neurologic signs on admission 35 days before death, received penicillin and streptomycin therapy for the endocarditis associated with infection by Streptococcus mitis. He became irrational and disoriented 12 days before death. An arteriogram performed 3 days before death did not show the left frontal lobe abscess. (Arteriograms failed to show a mass lesion in another
2 patients.) Multiple abscesses were found in 3 of the 5 patients with endocarditis. In 2 patients, Nocardia asteroides was recovered; in each patient, the abscesses were multiple. Of the 24 patients constituting the autopsy group, 9 ( 3 8 % ) had multiple abscesses. Five of the 24 patients had carcinoma, and, in most instances, the cerebral lesion was thought to be metastatic tumor. In 2 infants with congenital abnormalities, cerebral abscesses developed after overwhelming pneumonia. The details of 1 of the 24 patients whose abscess grew Corymebacterium hemolyticum have been reported by Washington, Martin, and Spiekerman (12). Discussion AGE AND SEX
Brain abscesses can occur at all ages of life. Our data show peak incidences in the first 2 decades of life and in the 2 decades between 50 and 70 years of age. Of the patients in the autopsy group, 3 3 % were older than 60 years, as were 20% of those in the surgical group. The men:women ratio in both groups combined was almost 2 : 1 ; this prevalence among men has been noted by others (3,4,6,13). CLINICAL PRESENTATION
Brain abscesses frequently present as expanding intracranial lesions, with headache and focal neurologic signs (3, 6, 7, 14), rather than as infectious processes. Fever is frequently absent (2, 3, 6, 7, 15).
Table 4. Organisms Isolated from Surgical Group
Organism
Isolates
As Part of Mixed Infection
As Single Isolate
Deaths
Major Neurologic Residual
— no. Aerobic organisms Streptococcus viridans Streptococcus pneumoniae Streptococcus group A Streptococcus group F Staphylococcus aureus Staphylococcus epidermidis Corynebacterium species Escherichia coli Enterobacter cloacae Enterobacter aerogenes Proteus species Hemophilus influenzae Hemophilus parainfluenzae Hemophilus aphrophilus Acinetobacter calcoaceticus Pseudomonas maltophilia Unclassified Gram-negative bacilli Actinobacillus actinomycetemcomitans Anaerobic organisms Peptostreptococcus Propionibacterium acnes Bacteroides species Bade wide s meIan ino genieus Bacteroides pneumosintes Eubacterium lentum Fusob acterium fusiforme Actinomyces israelii
18 1 2 1 7 1 3 1 1 1 1 2 2 2 2 1 3 2
7 0 0 1 1 1 3 0 1 0 0 2 1 2 2 1 3 1
11 1 2 0 6 0 0 1 0 1 1 0 1 0 0 0 0 1
3 0 0 0 0 1 0 0 0 0 1 0 0 1 0 0 0 1
4 0 1 0 3 0 1 0 0 0 0 0 1 0 0 1 1 1
10 5 2 1 1 1 1 1
8 5 2 1 1 1 1 0
2 0 0 0 0 0 0 1
4 1 0 0 0 0 0 1
4 0 1 0 0 0 0 0
Brewer et al. • Brain Abscess
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Table 5. Organisms Isolated from Brain Abscesses of Surgical Patients with Various Etiologic Infective Factors
Suspected Etiologic Factor
Organism Recovered
Otic or paranasal sinus infection
Streptococcus viridans, Streptococcus group A, Streptococcus pneumoniae, Staphylococcus aureus, Hemophilus aphrophilus, Enterobacter cloacae, Enterobacter aerogenes, Proteus species, Propionibacterium acnes, Peptostreptococcus, Eubacterium lentum, Bacteroides pneumosintes Streptococcus viridans, Streptococcus group F, Hemophilus parainfluenzae, Corynebacterium species, Peptostreptococcus, Propionibacterium acnes, Bacteroides species Streptococcus viridans, Pseudomonas maltophilia, Actinobacillus actinomycetemcomitans, Propionibacterium acnes, Peptostreptococcus, Actinomyces israelii, Bacteroides species Streptococcus group A, Staphylococcus aureus, Staphylococcus epidermidis, Hemophilus influenzae, Escherichia coli, Acinetobacter calcoaceticus, Peptostreptococcus, Bacteroides melan inogenie us Streptococcus viridans, Hemophilus parainfluenzae, Hemophilus aphrophilus, Propionibacterium acnes, Peptostreptococcus
Oral infection Pulmonary infection Head trauma or surgery
Congenital heart disease
bacillus actinomycetemcomitans, which is frequently found in lesions in association with A. israelii (21), was found in the brain abscesses of two patients, neither of whom, however, was found to have actinomycosis. Six of the eight staphylococcal isolates were recovered from the brain abscesses of patients who had sustained head trauma or who had had an operation. However, various other organisms were found in brain abscesses after head trauma or surgery (Table 5 ) ; as this table shows, Gram-negative aerobic and anaerobic organisms were recovered from patients with a variety of etiologic focuses of infection. These findings indicate that, despite knowledge of the underlying focus of infection, various organisms may be etiologic agents in brain abscesses. Furthermore, more than one organism was isolated from the brain abscesses of 32% of the patients in the surgical group. Therefore, the initial antibiotic program must cover a broad spectrum of organisms. Gram's stains of purulent material draining from the brain abscess recovered at operation, as well as information about organisms cultured from other focuses of infection, are helpful in planning the initial antibiotic regimen. However, empirical antibiotic therapy is indicated.
In general, the clinical presentation was more fulminating in the autopsy group of patients than in those of the surgical group. Severe neurologic disease or multisystem disease, or both, usually precluded a vigorous surgical approach. Five (21%) patients in the autopsy group had endocarditis. In at least one of them, the abscess appeared to progress, although the patient was receiving appropriate antibiotic therapy for endocarditis. Neurologic complications are not uncommon in patients with endocarditis (16), and endocarditis must be suspected in any instance of purulent infection of the central nervous system when the cause is not otherwise obvious. Patients being treated for endocarditis likewise should be observed closely during and immediately after treatment for the possible development of a neurologic lesion. The one patient in the surgical group who had endocarditis showed focal neurologic signs on the day after withdrawal of penicillin and streptomycin therapy for endocarditis due to infection with S. viridans. The two patients in the autopsy group who had infection with N. asteroides had obvious pulmonary involvement. Survival is notoriously poor with cerebral nocardiosis (reported mortality, 8 7 % ) (17). Recovery of this organism from any source in a patient with immunologic impairment or in patients with clinical evidence of infection calls for vigorous antimicrobial therapy. Appropriate therapy should be instituted according to the susceptibility of the organism in vitro, and the patient should be observed closely for evidence of central nervous system involvement (18).
THERAPEUTIC APPROACH TO BRAIN ABSCESS
Clinical findings and brain scanning may indicate early infective brain lesions in the stage of cerebritis ( 2 2 ) . Prompt diagnosis and vigorous antimicrobial therapy in the early stages of cerebritis may prevent abscess formation (23). However, because relapses requiring surgical intervention following medical therapy alone have been reported (23), patients treated expectantly by medical therapy alone must be observed closely for signs of deterioration or relapse. Black, Graybill, and Characbi (24) demonstrated viable organisms in brain abscesses despite therapeutically effective antibiotic concentrations in the abscesses. In our series, a brain abscess appeared to have progressed during appropriate therapy for endocarditis in one patient in the surgical group and in one patient in the autopsy group. Thus, surgical evacuation of brain abscesses is essential; antibiotic therapy alone is not sufficient. We believe that all brain abscesses should be treated surgically when they are diagnosed. Patients with cerebritis not responding to antimicrobial therapy undergo opera-
ASSOCIATED INFECTIONS AND ORGANISMS ISOLATED
A primary focus of infection could not be determined with confidence in 25% of the patients in the surgical group. Among those with another identifiable focus of infection, various microorganisms were recovered from the brain abscesses, regardless of the etiologic focus of infection (Table 5 ) . We noted, as have others (19), that brain abscesses not resulting from intracranial surgery or trauma frequently follow metastatic spread of infection from a focus of chronic suppuration. Hematogenous dissemination of Actinomyces israelii is a rare complication of actinomycosis (20, 2 1 ) . Actino574
April 1975
• Annals of Internal Medicine • Volume 82 • Number
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tion when signs of clinical deterioration appear. Abscesses involving vital brain centers are explored when the abscess appears to be threatening the life of the patient. When the etiologic focus of infection is in the mouth, ears, paranasal sinuses, lungs, or abdomen, or when the focus is indeterminate, a reasonable antibiotic regimen would consist of the administration of penicillin G, chloramphenicol, and gentamicin. We usually give these antibiotics, on a daily basis, as follows: penicillin G, 20 million units by intravenous infusion; chloramphenicol, 50 to 100 mg/kg body weight intravenously; and gentamicin, 5 to 6 mg/kg body weight either intramuscularly or intravenously. These doses are, of course, altered depending on associated disease or renal impairment. Streptococci are the most frequently isolated organisms from brain abscesses, and all except the enterococci are susceptible to penicillin G. Penicillin should be used in addition to chloramphenicol, because penicillin G is a bactericidal antibiotic, whereas chloramphenicol is not (25). The possibility of antimicrobial antagonism exists with the combination of penicillin G and chloramphenicol, but this is not a problem as long as penicillin therapy is started before or at the time of chloramphenicol (26). N o enterococci were isolated from the present series of patients; however, these organisms have been reported in cases of brain abscess ( 4 ) . Enterococcal infections usually require the synergistic action of penicillin plus an aminoglycoside to kill the organism (27). Bacteroides fragilis has been isolated previously from brain abscesses ( 1 9 ) , and, although no B. fragilis was identified in the present series, two of the Bacteroides isolates were not speciated. Bacteroides fragilis is usually resistant to penicillin and the aminoglycosides; however, chloramphenicol is an effective agent for this organism (28). Administration of both penicillin G and chloramphenicol—especially the latter— has been shown to produce effective concentrations in brain tissue (29). With gentamicin, there are no reliable studies, of which we are aware, that concern its concentration in brain tissue. The importance of the production of therapeutic levels of an antibiotic in the cerebrospinal fluid in the treatment of brain abscess is unknown. Penicillin G does not penetrate well into the cerebrospinal fluid in the absence of meningitis; however, this difficulty can be overcome by giving very high doses of this relatively nontoxic antibiotic (30). Chloramphenicol reaches a concentration in the cerebrospinal fluid that is 3 0 % to 5 0 % of the plasma concentration, even in the absence of meningeal inflammation (30). Gentamicin does not penetrate into the cerebrospinal fluid readily, and it has been recommended that, when this agent is used for the treatment of meningitis due to Gram-negative organisms, administration should be intrathecal as well as intravenous ( 3 1 ) . Because Gram-negative aerobic organisms have been isolated from brain abscesses in patients who have otic, paranasal sinus, or pulmonary infection, who have a history of complicating head trauma, or who have had an operation recently, gentamicin should be given until a microbiologic report is available. Both gentamicin (32)
Table 6. Diagnostic Procedures in Surgical Group
Procedure
Brain scan Computerized axial tomography Echoencephalogram Electroencephalogram Arteriogram Ventriculogram Pneumoencephalogram
Patients
Procedures with Abnormal Result
no.
no. (%)
8 1 18 37 47 8 4
8(100) 1 (100) 5(28) 33 (90) 44 (94) 8(100) 4(100)
and chloramphenicol (33,*) have antistaphylococcal activity that might be of value in unsuspected cases of infection with a penicillin-resistant staphylococcus. If an adjacent staphylococcal focus of infection is present, or if the brain abscess has developed after intracranial surgery or trauma, a penicillinase-resistant penicillin, such as oxacillin or methicillin, should be substituted for penicillin G in the triple-drug regimen. The initial antibiotic regimen should, of course, be altered when microbiologic data, including susceptibility studies, become available. The condition of two patients relapsed after they had received antibiotics postoperatively for 9 and 16 days. Except for one patient, no patient had a relapse after receiving antimicrobial therapy after operation for longer than 4 weeks; the one exception had a persistent otitis due to infection with S. aureus and had a recurrence, or reinfection, 4 years after the completion of a 31-day course of parenteral antimicrobial therapy. In view of Braude's (19) experience with two patients who had relapses after 2 and 3 weeks of antibiotic therapy, it seems reasonable to continue antimicrobial therapy for at least 4 weeks after operation to prevent relapse. DIAGNOSTIC STUDIES
Lumbar puncture in patients with possible brain abscesses should be discouraged. Frequently, only minimal information is obtained (2, 15, 19); the lethal complication of brain herniation has been repeatedly emphasized (2, 9, 15, 3 4 ) . Our data show that patients with brain abscesses not uncommonly present with purulent meningitis. If the history suggests the possibility of a ruptured brain abscess, the noninvasive technique of computerized axial tomography might rapidly demonstrate and localize the lesion. In our series, as well as those of others ( 3 , 14, 22, 35), brain scanning was both sensitive and accurate in showing these lesions. However, lesions less than 1 cm in diameter may not be seen by scanning, especially if these lesions are multiple ( 3 5 ) . Electroencephalography was more useful in our patients than has been reported by others (2, 9, 14). Arteriography, although reliable in this series and in others ( 3 ) , also may be misleading ( 3 6 ) . Computerized axial tomography with an E M I scannert was used in one case and accurately showed the lesion. This method may well become more important in the diagnosis and follow-up of patients with brain abscess. * SECTION OF CLINICAL MICROBIOLOGY, MAYO CLINIC: Unpublished data.
t EMI Limited, London, England. Brewer et a/. • Brain Abscess
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575
ADDITIONAL FACTORS INFLUENCING PROGNOSIS
Sperl, MacCarty, and Wellman (1) reported a higher mortality among patients with streptococcal infection. The striking mortality and morbidity in our surgical group were among those patients from whom anaerobic streptococci were isolated (Table 4 ) . These patients were affected by various predisposing factors and organisms. There is a possibility that anaerobic streptococci are particularly destructive to brain tissue. Liske and Weikers (4) also reported a particularly high mortality among patients with brain abscesses from which anaerobic streptococci were isolated. A high mortality among patients with multiple brain abscesses has been the experience of others ( 2 ) . In our series, 37% of the autopsy group as opposed to 13% of the surgical group had multiple brain abscesses. The eight patients with multiple brain abscesses in the surgical group accounted for 5 of the 10 surgical deaths. The recovery and identification of microorganisms— especially anaerobic organisms—from brain abscesses at the Mayo Clinic have improved since 1970. Improved recovery of anaerobic and fastidious organisms can best be attributed to more effective transport of specimens and more effective isolation procedures. It is to be hoped that in the future more accurate microbiologic data will lead to greater effectiveness of antimicrobial therapy and a decrease in operative mortality, which has not changed since 1959.
cedures in Clinical Microbiology, edited by WASHINGTON J A I I . Boston, Little, Brown & Company, 1974, p . 15 11. T H E ANAEROBE LABORATORY: Outline of Clinical Methods in Anaerobic Bacteriology. Blacksburg, Virginia Polytechnic Institute, 1970 12.
with Corynebacterium hemolyticum: report of a case. Am J Clin Pathol 56:212-215, 1971 13. KISER J L , KENDIG J H : Intracranial suppuration: a review of 139 consecutive cases with electro-microscopic observations o n three. J Neurosurg 20:494-511, 1963 14.
• Requests for reprints should b e addressed t o Nelson S. Brewer, M . D . , c / o Section of Publications, M a y o Clinic, Rochester, M N 55901.
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April 1975 • Annals of Internal Medicine • Volume 82 • Number 4
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