Positive blood cultures and diagnosis of bacterial meningitis in cases with negative culture of cerebrospinal fluid

The diagnosis of bacterial meningitis may be established through positive blood cultures in cases with negative culture of cerebrospinal fluid (CSF). However, information is sparse regarding how often the aetiological diagnosis is determined by blood culture alone. Therefore, we undertook a retrospective study of patients with meningitis and a blood culture-based bacterial diagnosis in North Jutland County, Denmark in 1997-2005. Patients were included if they had 1) a microscopy- and culture-negative CSF specimen with a leukocyte count > or =100x10(6)/l and an erythrocyte count < or =10,000x10(6)/l and 2) a positive blood culture within an interval of 3 d. A total of 20 patients fulfilled these criteria: 7 with Streptococcus pneumoniae, 4 with Neisseria meningitidis, 4 with Staphylococcus aureus, and 5 with miscellaneous bacteria. Suitable antibiotic therapy was delayed up to 48 h after lumbar puncture, and in-hospital mortality was 25%. A discharge diagnosis of bacterial meningitis was missing in 6/20 cases, and 12/20 cases had not been reported to Danish health authorities. Thus, patients with CSF-culture negative bacterial meningitis are at risk of delayed therapy, a poor outcome, and incomplete notification to health authorities.     

Bacterial meningitis with "normal" cerebrospinal fluid in adults: a report on five cases

Five adult patients with bacterial meningitis and normal cerebrospinal fluid (CSF) findings are described. All were patients in whom the lumbar puncture was performed very early in the course of the disease, or who had a low white blood cell count in peripheral blood. In such cases the diagnosis of bacterial meningitis may be overlooked.     

Vascular catheter-associated fungemia in patients with cancer: analysis of 155 episodes.

We reviewed all 155 episodes of central venous catheter-associated fungemia among inpatients at the National Cancer Institute during a 10-year period. Candida species accounted for 98% of episodes. Fungemia was documented by culture of blood drawn through catheters in 50% of cases and by culture of both catheter-drawn and peripheral blood in 39%; mortality and the rate of dissemination were similar for these two groups. Four management strategies were used: catheter removal, antifungal therapy (with amphotericin B), both, or neither; indications for the use of both modes of treatment included fever, neutropenia, long-term indwelling catheterization, positive cultures of both catheter-drawn and peripheral blood, isolation of Candida tropicalis, and fungal isolation from two or more blood cultures. Disseminated fungal infection was documented in 82% of cases with these features but also in 35% of the less severe cases treated only with catheter removal. In addition, nine (82%) of 11 cases managed only with antifungal therapy had a negative outcome (either death from disseminated infection or the recurrence of fevers and/or fungemia), a finding suggesting that intravascular catheters should be removed in fungemia. Virtually all cases of catheter-associated fungemia in patients with cancer are clinically significant and require prompt therapy with amphotericin B.     

Cryptococcosis in HIV-infected children

Between January 1994 and December 2001, 21 HIV-infected children were diagnosed as having cryptococcosis. The 8-year point prevalence of cryptococcosis among hospitalized HIV-infected patients was 2.97%. Medical records of 19 patients were available for review. Sixteen patients had cryptococcal meningitis. Of these patients, cryptococcal antigen in the cerebrospinal fluid and sera were positive in all tested samples. India ink preparations were positive in 94% of cases. However, the routine CSF examination was normal in 50% of cases. All patients but one received antifungal treatment. Six patients died during treatment, the others (13 patients) were successfully treated. Relapse occurred in 2 patients despite secondary prophylaxis. Two patients died later from other causes and nine were lost to follow-up. We conclude that cryptococcal meningitis was the most common clinical presentation of cryptococcosis among HIV-infected children. HIV-infected children who present with fever, with or without central nervous system signs, should have a lumbar puncture and CSF sent for cryptococcal antigen and culture.     

The role of lumbar puncture in the evaluation of dementia: the University of Pittsburgh Study

In a retrospective study of 80 patients over 55 years old, the efficacy of lumbar puncture in evaluating elderly demented patients was examined. Despite a cost of $381 per procedure, in addition to cerebrospinal fluid (CSF) evaluation, no diagnosis was made on the basis of the information obtained in any of the patients (53 per cent) who underwent lumbar puncture. The only abnormalities found were 11 cases of nonspecific elevations in CSF protein and one case of abnormal cellularity not related to bacterial infection. An additional 422 cases of dementia from other series were reviewed, and only four patients were found whose diagnosis could have been made by lumbar puncture--one patient had neurosyphilis, and the other three were postencephalitic. In addition, the literature on complications of lumbar puncture was reviewed. There were no serious complications of lumbar puncture in the present study. The authors concluded that although it is low-risk, lumbar puncture cannot currently be recommended for routine use in the evaluation of elderly demented patients, but should be used in evaluating demented patients under 55 years of age, patients with rapid onset or progression of dementia, patients with syphilis serology in suspected cases of viral encephalitis, and patients with signs and symptoms of fungal meningitis.     

Role of empiric parenteral antibiotics prior to lumbar puncture in suspected bacterial meningitis: state of the art

The performance of lumbar puncture (LP) in patients with suspected meningitis is often delayed if, for example, the clinical presentation suggests a need for prior computed tomographic (CT) scan or if patients are initially examined at settings with limited clinical facilities. The role of empiric parenteral antibiotic therapy prior to LP under these circumstances has not been critically analyzed. Review of the literature suggests that in cases of bacterial meningitis (1) the existing data are inadequate to assess the effect of a short delay of therapy on mortality and morbidity; (2) a short period of antibiotic therapy prior to LP does not change cerebrospinal fluid (CSF) white blood cell count, protein, or glucose; (3) the yield of CSF gram stain and culture may be somewhat reduced by a short period of antibiotic therapy, but these tests often remain positive; and (4) adjunctive tests, including blood cultures and CSF antigen tests, can often independently identify the bacterial meningopathogen. The available evidence suggests that if bacterial meningitis is suspected and LP must be delayed, intravenous antibiotics are warranted before CSF is obtained.     

Invasion of the central nervous system by Treponema pallidum: implications for diagnosis and treatment

STUDY OBJECTIVES: To determine the prevalence of Treponema pallidum in cerebrospinal fluid (CSF) of patients with syphilis, to determine the effect of concurrent HIV infection on central nervous system involvement by T. pallidum, and to examine the efficacy of conventional therapy for asymptomatic neurologic involvement. PATIENTS: Fifty-eight patients with untreated syphilis who consented to lumbar puncture, representing approximately 10% of new cases of syphilis during the study period. INTERVENTIONS: Lumbar puncture was done on all patients. Rabbit inoculation was used to test cerebrospinal fluid for viable T. pallidum. Patients with normal fluid received recommended benzathine penicillin therapy according to the stage of syphilis; patients with CSF abnormalities were offered 10-day therapy for neurosyphilis. RESULTS: Treponema pallidum was isolated from the CSF of 12 (30%) of 40 patients (95% CI, 17 to 46) with untreated primary and secondary syphilis; isolation of T. pallidum was significantly associated (P = 0.008) with the presence of two or more abnormal laboratory variables (among leukocyte count, protein concentration, and CSF-Venereal Disease Research Laboratory [VDRL] test). Two (67%) of 3 early latent (CI, 13 to 100) and 3 (20%) of 15 late latent syphilis patients (CI, 5 to 47) also had reactive CSF-VDRL tests and elevated cell and protein levels, although T. pallidum was not isolated. Concurrent infection with the human immunodeficiency virus (HIV) was not associated with isolation of T. pallidum, increased number of CSF abnormalities, or reactive CSF serologic tests for syphilis, although CSF pleocytosis was commoner in subjects infected with HIV. Treatment with conventional benzathine penicillin G (2.4 mIU) failed to cure 3 of 4 patients with secondary syphilis from whom T. pallidum was isolated before therapy; all 3 patients in whom treatment failed were HIV seropositive when treated or seroconverted during follow-up. CONCLUSIONS: Central nervous system invasion by T. pallidum is common in early syphilis, and is apparently independent of HIV infection. Examination of the CSF may be beneficial in patients with early syphilis, and therapy should be guided by knowledge of central nervous system involvement. Conventional benzathine penicillin G therapy may have reduced efficacy in patients with early syphilis who are also infected with HIV.     

The value of serum cryptococcal antigen in the diagnosis of cryptococcal infection in patients infected with the human immunodeficiency virus

Serum cryptococcal antigen titres were measured in 828 HIV-infected patients with pyrexia, 69 of whom had meningism. Serum cryptococcal antigen was positive in 17 patients of whom 16 had meningism with cryptococcus isolated from their CSF. The other patient had no meningism, had no evidence of cryptococcal infection on repeated CSF examination and remains well. A positive serum cryptococcal antigen test was therefore valuable in the diagnosis of cryptococcal meningitis, although in all 16 patients meningism was present and a diagnostic lumbar puncture was therefore carried out. In our experience routine screening for serum cryptococcal antigen did not predict patients who subsequently developed cryptococcal meningitis.     

A rostral-caudal concentration gradient in cerebrospinal fluid adrenocorticotropin

In two separate experiments, cerebrospinal fluid (CSF) adrenocorticotropin immunoreactive (ACTH-IR) concentrations in the rhesus monkey followed a significant rostral-caudal gradient. In the first study, CSF was sampled from an indwelling catheter in awake animals. The mean ACTH-IR concentration in the cisternal region was 12.3 pg/ml, as compared to 8.56 pg/ml in the lumbar region. In the second study, CSF was sampled in a different group of monkeys by percutaneous puncture at the cisterna magna and at L5-L6. In this study, the mean ACTH-IR concentration in samples collected from the cistern was also greater than the concentration from L5-L6. In addition, a significant correlation within subjects was found between samples collected from the two sites (r = 0.86). These results demonstrate that the site of CSF sampling is a variable in determining CSF ACTH-IR concentrations and suggest that lumbar CSF ACTH-IR concentrations in humans may be interpreted as indexes of ACTH changes at higher levels in the central nervous system.     

Distinguishing cerebrospinal fluid abnormalities in children with bacterial meningitis and traumatic lumbar puncture

The characteristics of cerebrospinal fluid (CSF) associated with traumatic lumbar puncture, defined as CSF red blood cell (RBC) count greater than 1000/mm3, were reviewed in 92 previously healthy children greater than 1 month of age; 30 had bacterial meningitis and 62 had negative CSF cultures. The purpose was to distinguish CSF profiles of the two groups despite contamination with peripheral blood elements. In each case, white blood cell (WBC) counts were observed (O) and compared with those predicted (P), calculated as P = CSF RBC X (blood WBC/blood RBC). Comparison of O:P ratios revealed that all 30 patients with bacterial meningitis had ratios greater than or equal to 1, 28 (93%) had ratios greater than 10, and 24 (80%) had ratios greater than 100; by contrast, only 2 patients (3%) with culture-negative CSF had ratios greater than 10, 21 (34%) had ratios of 1-10, and 39 (63%) had ratios less than 1. Significant differences were observed in the rate of O:P ratio greater than or equal to 1 (100% vs. 32%), CSF differential cell count predominance of polymorphonuclear leukocytes (97% vs. 11%), hypoglycorrhachia (73% vs. 3%), and positive Gram's-stained smear for pathologic organisms (80% vs. 0) in those with and without bacterial meningitis, respectively (P less than .0001). Thus, in children greater than 1 month of age, CSF abnormalities associated with bacterial meningitis are rarely obscured by blood contamination from traumatic lumbar puncture.     

Changing Bacteriology of Periorbital Cellulitis

Study objective: Bacteremic periorbital cellulitis has traditionally been associated with Haemophilus influenzae infection, and the recommended diagnostic evaluation in young children includes blood culture and cerebrospinal fluid (CSF) analysis. The objectives of this study were to examine in pediatric patients with periorbital cellulitis (1) the prevalence of H influenzae bacteremia in the era of vaccination for H influenzae type B (HIB) and (2) the yield of routine CSF analysis. Methods: This was a retrospective case series of children aged 2 months to 17 years with a final discharge diagnosis of periorbital cellulitis who were treated from 1986 through 1994 at an urban university referral hospital. The prevalence of bacteremia and meningitis was obtained from chart review. Results: Forty-nine children were enrolled, of whom 3 were treated as outpatients. The mean age was 36 months (median, 19 months). A blood culture was obtained for 92% of the patients. Five patients (10%; 95% confidence interval, 3% to 22%) had a positive blood culture (four streptococcal species, one H influenzae). The patient with H influenzae bacteremia was treated in 1987 and had not had the HIB vaccine. CSF was analyzed for 41% of the patients, and none had an abnormal cell count or a positive culture. Sinusitis was diagnosed radiographically in 19% of the subjects. Conclusion: Streptococcal organisms are the most common cause of bacteremia associated with periorbital cellulitis in the post-HIB vaccination era. H influenzae bacteremia is now a rare occurrence. Meningitis is uncommon, and lumbar puncture may not be mandatory in well-appearing children. Sinusitis is common and was probably underdiagnosed in our series because most children were not evaluated radiographically. Outpatient management may be indicated in selected children. [Schwartz GR, Wright SW: Changing bacteriology of periorbital cellulitis. Ann Emerg Med December 1996;28:617-620.]     

Clinical characteristics, treatment and prognostic factors of candidal meningitis in a teaching hospital in Taiwan

The prognostic factors of candidal meningitis had rarely been studied owing to the rarity of this disease. We identified 17 patients with candidal meningitis at a teaching hospital in Taiwan over a 14-y period and give details of the clinical features, treatment, outcome and prognostic factors of this disease. 10 patients were children (1 was neonate) and 7 were adults. The clinical features and cerebrospinal fluid (CSF) findings were non-specific. The disease was diagnosed > 72 h after hospitalization in 14 (82%) patients. The most frequently isolated species was Candida albicans (65%). Regimens of therapy included intravenous amphotericin B deoxycholate (AmB) or fluconazole alone, or a combination of intravenous AmB with intrathecal AmB, flucytosine or fluconazole. All indwelling central nervous system devices were externalized or removed. Four adults died of the disease. Three of them had malignancy and had received < 48 h of antifungal therapy. For adult patients with malignancy, early diagnosis and alternative treatment modalities with newer antifungal agents may be needed.     

A murine model of coccidioidal meningitis

Coccidioidal meningitis is lethal in humans. A reproducible murine model was established by lumbar intrathecal injection of Coccidioides immitis arthroconidia. Cerebrospinal fluid (CSF) samples were obtained by cisternal puncture. Lethal infection developed in all mice given 10-60 colony-forming units (cfu). Lethargy, ataxia, or paralysis preceded death. Temporal studies after challenge with 27 cfu revealed positive brain (4/5 mice) and spinal cord (2/5 mice) cultures on day 3; CSF samples contained 688 leukocytes/mm(3) and 33 cfu/mL. The results of histopathologic analysis were unremarkable. By day 8, all mice were culture positive (5.0 log(10) cfu in brain tissue and 4.1 log(10) cfu in spinal cord tissue); CSF samples contained 4833 leukocytes/mm(3) and 3425 cfu/mL. Histopathologic examinations showed acute meningitis of the brain and spinal cord, some parenchymal invasion and abscesses, and meningeal arteritis. Groups of mice given ketoconazole had prolonged survival and suppressed lung disease; histopathologic examination demonstrated granulomatous meningitis, possibly a more chronic form. With the development of these models, studies of pathogenesis, host response, and therapy are possible.     

Clinical utility of blood cultures drawn from indwelling central venous catheters in hospitalized patients with cancer

BACKGROUND: Because of concern about low specificity, the American College of Physicians guidelines and expert opinion discourage the use of a central venous catheter when obtaining blood for culture for bacteremia or fungemia. However, data on the reliability of cultures done with blood obtained from a central venous catheter are conflicting. OBJECTIVE: To determine the sensitivity, specificity, and positive and negative predictive values of cultures done with blood obtained through a central venous catheter compared with peripheral venipuncture. DESIGN: Retrospective cohort study of hospitalized patients with cancer in whom samples for paired cultures were drawn through a central venous catheter and peripheral venipuncture. SETTING: Tertiary care, university-affiliated medical center. PATIENTS: 185 patients hospitalized on a hematology-oncology ward between August 1994 and June 1996. MEASUREMENTS: Blinded assessments of culture results done by infectious disease experts were used as the gold standard. Sensitivity, specificity, and positive and negative predictive values were compared for culture of blood from central catheters and culture of blood from peripheral venipuncture. RESULTS: Of 551 paired cultures, 469 (85%) were catheter-negative/venipuncture-negative, 32 (6%) were catheter-positive/venipuncture-positive, 17 (3%) were catheter-negative/venipuncture-positive, and 33 (6%) were catheter-positive/venipuncture-negative pairs. For the 82 paired cultures with at least one positive result, blinded determination of true bacteremia or fungemia was made by two infectious disease specialists. For catheter draw compared with peripheral venipuncture, sensitivity was 89% (95% CI, 79% to 98%) and 78% (CI, 65% to 90%) (difference, 11 percentage points [CI, -6 to 28 percentage points]), specificity was 95% (CI, 93% to 97%) and 97% (CI, 96% to 99%) (difference, -2 percentage points [CI, -5 to 0.2 percentage points]), positive predictive value was 63% (CI, 50% to 75%) and 73% (CI, 60% to 86%) (difference, -10 percentage points [CI, -26 to 5 percentage points]), and negative predictive value was 99% [CI, 97% to 100%]) and 98% (CI, 96% to 100%) (difference, 1 percentage point [CI, -0.5 to 3 percentage points]). CONCLUSIONS: In hospitalized hematology-oncology patients, culture of blood drawn through either the central catheter or peripheral vein shows excellent negative predictive value. Culture of blood drawn through an indwelling central venous catheter has low positive predictive value, apparently less than from a peripheral venipuncture. Therefore, a positive result from a catheter needs clinical interpretation and may require confirmation. However, the use of a catheter to obtain blood for culture may be an acceptable method for ruling out bloodstream infections.     

Pseudo-Outbreak of Ventriculitis in a Neurosurgical ICU

BACKGROUND: Infection is a potentially life-threatening complication of ventriculostomy placement. Placement of ventricular catheters frequently occurs outside the setting of the operating room. We typically detect <10 nosocomial central nervous system infections per year in our neurosurgical ICU. Over a 4–month period (May–August 2003), 19 positive cerebrospinal (CSF) cultures were noted in 10 patients. Organisms included coagulase-negative staphylococci (CNS, 16 cultures in 7 patients), Pseudomonas aeruginosa (4 cultures in 2 patients), and Acinetobacter lwoffi (1 culture in 1 patient).METHODS: An outbreak investigation was performed, including review of the patients' clinical course, laboratory data, ventriculostomy catheter insertion, site care, CSF specimen collection practices, and interviews with all involved staff.RESULTS: Investigation revealed ventriculostomy CSF specimens were collected by a single neurosurgical resident each month. Five (50%) of the patients were determined to have infection. CNS was found in all (10) contaminated cultures. Of 66 cultures obtained in August, 17 (26%) were culture positive, and 9 (14%) of these were contaminated. One resident obtained all cultures in August. Meetings were held between epidemiology department, neurosurgery faculty, and nursing staff. Practice changes were implemented to emphasize hand hygiene, aseptic collection techniques, and exit site care. Inservices were held for nursing staff and neurosurgery residents. Subsequent review of CSF cultures has revealed no further contamination.CONCLUSIONS: Continuing education of medical and nursing staff is required to prevent poor collection technique to prevent contamination of CSF obtained from ventriculostomy catheters. When investigating a potential outbreak, it is important to review all laboratory and clinical data to ensure that positive culture results represent true infection.     

Meningococcal meningitis with ‘normal’ cerebrospinal fluid

A prospective study was made of all patients with normal CSF counts and positive cultures for Neisseria meningitidis diagnosed in “El Vallés” County, Barcelona between January 1987 and December 1990. Meningococcal meningitis was documented in 82 patients, eight of whom (seven children, five boys and two girls with a mean age of 5·6 ± 3·3 years, and a 69-year-old male patient) had no apparent CSF abnormalities in the initial lumbar puncture. At the time of admission all patients had fever (mean 39·1 °C) of 10·8 ± 5·6 hour duration and petechial rash which had been present for a mean of 3·6 ± 3·3 hours. Signs of meningeal irritation were not found. A 4-month-old infant with symptoms of circulatory collapse, intracranial hypertension and impairment of consciousness subsequently died of septicemia in 48 hours. Group B N. meningitidis was isolated in six cases (reduced penicillin-susceptibility in two cases) and group C N. meningitidis in the remaining two (reduced penicillin-susceptibility in one case). Patients without pleocytosis did not differ in a statistically significant fashion from the patients with high pleocytosis in the duration of temperature, and petechial rash, leukopenia, positive blood culture and fatal outcome.     

Clinical features, laboratory findings and management of meningococcal meningitis in England and Wales: report of a 1997 survey. Meningococcal meningitis: 1997 survey report

OBJECTIVES: To describe the epidemiological, clinical and laboratory features of meningococcal meningitis and the effects of antibiotics on laboratory investigations under current clinical practices in England and Wales. METHODS: Using a telephone questionnaire, information was gathered on 103 cases with a clinical diagnosis of meningococcal meningitis. Included were cases with samples submitted to the Public Health Laboratory Service (PHLS), Meningococcal Reference Unit (MRU) over a 5-month period in 1997. Tests included microscopic examination, latex agglutination and culture for Neisseria meningitidis, and at MRU confirmation of identification and characterization of isolates and meningococcal polymerase chain reaction (PCR) analysis on blood and cerebrospinal fluids (CSF). RESULTS: Clinically 45% of the cases had predominantly meningitis and 55% had septicaemia and meningitis. Only 29% of the cases received pre-admission benzylpenicillin, and 66% were given antibiotics within an hour of hospital attendance. Microbiological confirmation was achieved in 97 cases, 46 (44%) by traditional tests and 92 (89%) by PCR assay, including some with both. The blood culture positive rate was 23 (22%), but in predominant meningitis the rate was only 10% (5/46). PCR was the sole method of confirmation in 48 cases. Seventy percent of the plasma samples referred were reactive by PCR assay, but all samples taken more than 24 h after hospital antibiotics were non-reactive. PCR-based techniques increased the overall number of cases with a serogroup identified by 44%. Lumbar punctures were performed in 73 of the cases and microbiological confirmation was achieved in 67 (92%) of these cases, compared to 26/30 without lumbar puncture (LP). Eighty-nine percent of the CSF samples referred were reactive by PCR; 50% of the CSF samples taken more than 24 h after hospital antibiotics were reactive, whilst none were positive by culture or microscopy. CONCLUSION: Due to variable clinical manifestations, early diagnosis and treatment was difficult. Laboratory confirmation has been improved by the introduction of PCR-based techniques. Meningococcal DNA was detected by molecular methods in CSF samples taken up to 72 h after commencement of antibiotics. During this period patients could be stabilized and the chances of complications attendant upon early LP reduced. In addition to providing accurate epidemiological information, confirming the diagnosis may alter the extent and length of follow-up.     

Traumatic lumbar puncture at diagnosis adversely affects outcome in childhood acute lymphoblastic leukemia

The effect of traumatic lumbar puncture at the time of initial diagnostic workup on treatment outcome in children with newly diagnosed acute lymphoblastic leukemia (ALL) was investigated. The findings of the first 2 lumbar punctures performed on 546 patients with newly diagnosed ALL treated on 2 consecutive front-line studies (1984-1991) at St Jude Children's Research Hospital were retrospectively reviewed. Lumbar punctures were performed at the time of diagnosis and again for the instillation of first intrathecal chemotherapy. The event-free survival (EFS) experience for patients with 1 cerebrospinal fluid (CSF) sample contaminated with blast cells was worse than that for patients with no contaminated CSF samples (P =.026); that of patients with 2 consecutive contaminated CSF samples was particularly poor (5-year EFS = 46 +/- 9%). In a Cox multiple regression analysis, the strongest prognostic indicator was 2 consecutive contaminated CSF samples, with a hazard ratio of 2.39 (95% confidence interval, 1. 36-4.20). These data indicate that contamination of CSF with circulating leukemic blast cells during diagnostic lumbar puncture can adversely affect the treatment outcome of children with ALL and is an indication to intensify intrathecal therapy.     

A pilot study of the discontinuation of antifungal therapy for disseminated cryptococcal disease in patients with acquired immunodeficiency syndrome, following immunologic response to antiretroviral therapy

To determine whether microbiologic cure of acquired immunodeficiency syndrome (AIDS)-related disseminated cryptococcosis is possible in patients receiving highly active antiretroviral therapy (HAART), antifungal therapy was discontinued in 6 patients with a history of disseminated cryptococcosis who had received > or =12 months of antifungal therapy. All were asymptomatic and had absolute CD4+ T cell counts of >150 cells/microL (range, 178-525 cells/microL). Blood, cerebrospinal fluid (CSF), and urine samples were obtained for fungal culture. Serum and CSF cryptococcal antigen titers were also obtained. All 6 patients had CSF and blood cultures negative for Cryptococcus neoformans and were receiving HAART. All patients' subsequent cultures remained sterile, and all patients were clinically asymptomatic 24 months after ending antifungal therapy. Disseminated cryptococcal disease can be cured by prolonged antifungal therapy in some patients with AIDS who experience sustained CD4 lymphocyte increases while receiving HAART.     

Serial cerebrospinal fluid corticotropin-releasing hormone concentrations in healthy and depressed humans.

CRH, a hypothalamic peptide that is the most potent ACTH secretagogue known, also appears to be produced in the cerebral cortex and spinal cord. Depressed patients have blunted responses to exogenous CRH and normal to high concentrations of CRH immunoreactivity in single morning samples of lumbar cerebrospinal fluid (CSF). Although these data suggest that depression may be associated with hypersecretion of CRH, it has also been postulated that central nervous system insufficiency of CRH might have a pathophysiological role in certain depressive syndromes. We continuously sampled lumbar CSF via indwelling subarachnoid catheters from 1100-1700 h and measured CRH at 10-min intervals in depressed patients and normal subjects. A standardized mixed liquid meal was administered at 1300 h. CSF CRH was strikingly reduced in depressed patients compared to normal subjects [4.2 +/- 1.1 pmol/L vs. 13 +/- 2.1 pmol/L (mean +/- SEM), respectively, P less than 0.01 by Wilcoxon test]. CSF CRH concentrations rose progressively during the experiment in both groups, suggesting a diurnal rhythm and, possibly, response to a test meal. CRH had a very brief half-life in CSF (less than 10 min), suggesting that the spinal cord is the origin of CRH in lumbar CSF. The rapid transients in CSF CRH concentration demonstrate that single samples provide very limited information. There were no intraindividual correlations between CSF CRH concentrations and those of either plasma ACTH or cortisol, both of which rose in response to eating. The present data show that impaired central nervous system secretion of CRH can exist during states of severe depression.