Patient outcomes and surgical complications in coccidioidomycosis-related hydrocephalus: an institutional review

Clinical article

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Object

Coccidioidomycosis is a common fungal infection in the southwestern US. Hydrocephalus is a serious complication of cranial coccidioidomycosis, and the surgical management of coccidioidomycosis-related hydrocephalus has unique challenges. The authors reviewed their institutional experience with hydrocephalus in the setting of coccidioidomycosis.

Methods

The authors retrospectively identified 44 patients diagnosed with coccidioidomycosis-related hydrocephalus at their institution since 1990, who underwent a total of 99 shunting procedures. The authors examined patient demographics, type of shunt and valve used, pressure settings, failure rates, medical treatment, ventricular response to shunting, and other variables.

Results

The majority of patients were young (average age 37 years) men (male/female ratio 28:16) with a mean follow-up of 63 months. Patients of Asian and African descent were overrepresented in the cohort compared with regional demographic data. The overall shunt failure rate during follow-up was 50%, and the average number of revisions required if the shunt failed was 2.5 (range 1–8). Low to moderate draining pressures (mean 88 mm H2O) were used in this cohort. Fourteen patients received intrathecal antifungals, and a trend of initiating intrathecal therapy after need for a shunt revision was observed (p = 0.051). The majority of shunt failures (81%) were due to mechanical blockages in the drainage system. Most patients (59%) had at least partial persistent postoperative ventriculomegaly despite successful CSF diversion. Four patients (9%) died due to coccidioidomycosis during the follow-up period.

Conclusions

Coccidioidomycosis-related hydrocephalus more often affected young males in the study's cohort, especially those of African and Asian descent. Despite the best medical therapy, there was a high rate of shunt failure due to clogged catheters or valves due to the underlying disease process. Many patients continued to have ventriculomegaly even with adequate CSF diversion. The morbidity and mortality of this chronic disease process must be recognized by the treatment team, and patients should be appropriately counseled.

Abstract

Object

Coccidioidomycosis is a common fungal infection in the southwestern US. Hydrocephalus is a serious complication of cranial coccidioidomycosis, and the surgical management of coccidioidomycosis-related hydrocephalus has unique challenges. The authors reviewed their institutional experience with hydrocephalus in the setting of coccidioidomycosis.

Methods

The authors retrospectively identified 44 patients diagnosed with coccidioidomycosis-related hydrocephalus at their institution since 1990, who underwent a total of 99 shunting procedures. The authors examined patient demographics, type of shunt and valve used, pressure settings, failure rates, medical treatment, ventricular response to shunting, and other variables.

Results

The majority of patients were young (average age 37 years) men (male/female ratio 28:16) with a mean follow-up of 63 months. Patients of Asian and African descent were overrepresented in the cohort compared with regional demographic data. The overall shunt failure rate during follow-up was 50%, and the average number of revisions required if the shunt failed was 2.5 (range 1–8). Low to moderate draining pressures (mean 88 mm H2O) were used in this cohort. Fourteen patients received intrathecal antifungals, and a trend of initiating intrathecal therapy after need for a shunt revision was observed (p = 0.051). The majority of shunt failures (81%) were due to mechanical blockages in the drainage system. Most patients (59%) had at least partial persistent postoperative ventriculomegaly despite successful CSF diversion. Four patients (9%) died due to coccidioidomycosis during the follow-up period.

Conclusions

Coccidioidomycosis-related hydrocephalus more often affected young males in the study's cohort, especially those of African and Asian descent. Despite the best medical therapy, there was a high rate of shunt failure due to clogged catheters or valves due to the underlying disease process. Many patients continued to have ventriculomegaly even with adequate CSF diversion. The morbidity and mortality of this chronic disease process must be recognized by the treatment team, and patients should be appropriately counseled.

Coccidioides immitis is a soil fungus endemic to the southwestern US and usually causes a self-limiting influenza-like illness in humans. In a small number of patients, hematological spread leads to disseminated coccidioidomycosis, which can affect nearly all organ systems in both immunologically normal and immunocompromised hosts.10 Despite modern lifelong antifungal therapy, coccidiodomycosis is rarely cured.5 Relevant to the field of neurosurgery, disseminated coccidioidomycosis may lead to fungal meningitis, cerebral or spinal abscess formation, and/or spinal osteomyelitis/discitis.6,8,12 Meningitis due to coccidioidomycosis is often chronic and may lead to stroke due to vascular compromise at the skull base.2,7 Hydrocephalus due to arachnoid scarring is also a common sequela of coccidioidomycosis and may require CSF diversion via shunting.1,3,4,9,11 One large series reported that approximately half of patients with coccidioidomycosis meningitis developed hydrocephalus.4 The benefits of shunting must be appropriately weighed against the risk of placing indwelling hardware in a chronically infected patient. Due to a paucity of literature on the subject, we retrospectively reviewed our tertiary center's experience with managing coccidioidomycosis-related hydrocephalus.

Methods

We identified all patients treated at the Barrow Neurological Institute between 1990 and 2013 who were diagnosed with disseminated CNS coccidioidomycosis via an interdisciplinary registry after appropriate institutional review board approval was obtained from St. Joseph's Hospital and Medical Center. All patients had CSF serology and/or culture confirming the diagnosis of CNS coccidioidomycosis. The registry was used to identify all patients who underwent a CSF diversion procedure. Hospital, outpatient neurosurgical, and infectious disease clinic and radiological records were reviewed. Patient data such as age at diagnosis, race, gender, presentation, immunological status (normal vs compromised), radiographic findings, procedure(s) performed, antifungal therapies used, and morbidity/mortality were recorded. Each patient's clinical and radiographic records were analyzed for number of the CSF diversion operations, reasons for shunt failure, shunt pressure settings, and shunt valve brand, and the results were stratified by shunting procedure. We also sought to quantify the ventricular system response to shunting and divided postoperative imaging in those patients with full response to CSF diversion (normal postoperative ventricular size), partial response (decrease in ventricular size but chronic postoperative ventriculomegaly), or no response (stably enlarged ventricular size postoperatively despite a working shunt system and appropriate pressure settings). Postoperative imaging was not standardized; rather, it was directed by the treating physicians and tailored to patient symptoms. However, included postoperative imaging had to be performed at least 1 month after the index shunt procedure to allow time for ventricular reconfiguration. For statistical analysis, Fisher exact tests were used to compare categorical characteristics, while Student t-tests were used to assess continuous variables. A p value < 0.05 was considered statistically significant.

Results

Patient Demographics

We identified 44 patients with confirmed CNS coccidioidomycosis who underwent 99 CSF diversion procedures at our institution between 1990 and 2013. Their demographic information is presented in Table 1. The majority of patients were young men (mean age 37 years; male/female ratio 28:16). Only a small minority of patients were immunocompromised due to human immunodeficiency virus or chronic renal dialysis (n = 6, 13.6%). Patients of African/African American (OR 6.4 compared with Caucasian patients, 95% CI 2.1–19.0, p = 0.0002) and Asian/Pacific Islander (OR 5.2 compared with Caucasian patients, 95% CI 1.5–18.4, p = 0.006) race were significantly overrepresented in the patient cohort when compared with Arizona census demographics (http://quickfacts.census.gov). The odds ratios for Native American and Hispanic heritage patients did not significantly differ from Caucasian patients (Table 2). All patients were maintained on chronic oral antifungal therapy. Fourteen patients (32%) were maintained on intrathecal antifungals at some point during their treatment. The mean clinical follow-up period after the first shunting operation was 63 months (range 4.1–315 months), during which 4 patients (9%) died due to coccidioidomycosis. One patient died as a result of ischemic stroke due to progressive basilar meningitis, 1 patient died of medical complications following transtentorial herniation due to acute shunt failure, and 2 patients were discharged to hospice due to progressive global neurological decline despite adequate CSF diversion.

TABLE 1:

Patient demographics

ParameterValue (range or %)
mean age at diagnosis37 (15–68) yrs
mean clinical follow-up63 (4.1–315) mos
male/female28:16
race
 Native American2 (5.3%)
 Asian/Pacific Islander5 (13.1%)
 Hispanic7 (18.4%)
 African/African American8 (21.1%)
 Caucasian/non-Hispanic16 (42.1%)
 unknown6 (13.6%)
immunocompromised6 (13.6%)
intrathecal antifungals14 (31.8%)
chronic oral antifungals44 (100%)
mortality4 (9%)
TABLE 2:

Summary of race distribution among patients with coccidioidomycosis-related hydrocephalus

RaceNo. of Patients, Current Series*Arizona 2012 CensusOR vs Caucasian Patients (95% CI)p Value
Native American2 (5.3%)5.3%1.4 (0.4–4.8)0.74
Asian5 (13.1%)3.4%5.2 (1.5–18.4)0.006
Hispanic7 (18.4%)30.2%0.8 (0.4–1.7)0.6
African8 (21.1%)4.5%6.4 (2.1–19.0)0.0002
Caucasian16 (42.1%)57.1%

Percentiles calculated based on 38 patients with known races.

Fisher exact test compared to Caucasian patients, 2-tailed.

Hydrocephalus and Shunting Outcomes

All patients, by inclusion criteria, underwent CSF diversion via shunt placement (Table 3). The majority of patients had ventriculoperitoneal shunts at their last follow-up (n = 40, 91%), although ventriculoatrial (n = 4, 9%) shunts were used in a small minority of patients. Low to moderate draining pressures were used in this cohort (mean draining pressure, 88 mm H2O), as measured by shunt setting recorded at last clinical follow-up. Valve selection was directed by individual surgeon preference, and these included valves from Hakim and Certas (both Codman Neuroscience Therapies, Raynham, MA), proGAV (Aesculap, Center Valley, PA), Strata (Medtronic Neurosurgery, Goleta, CA), and Polaris (Sophysa, Crown Point, IN). In the clinical record, valve brand was recorded for 86 of the 99 included operations. Only 4 of the 86 identified valves were nonprogrammable. With regard to ventricular response to shunting, all but 3 patients (n = 41) had pre- and postoperative CT and/or MR imaging to quantify ventricular response (examples are shown in Fig. 1). A significant number of patients had a positive ventricular response to shunting (n = 17, 41%) with resolution of preoperative ventriculomegaly (Fig. 1A and B). However, many patients experienced only a partial decrease (n = 15, 37%) in ventricular size with persistent postoperative ventriculomegaly despite a working shunt and attempts at alteration in valve setting (Fig. 1C and D). A third subset of patients (n = 9, 22%) exhibited no significant decrease in ventricular size after shunting as assessed by long-term radiographic follow-up, despite a functional shunt system (Fig. 1E and F). Therefore, a majority of patients (n = 24, 59%) had at least partial persistent ventriculomegaly after successful CSF diversion. There were no differences among the three ventricular response groups with regard to mean valve draining pressures, number of revisions required, or valve brands.

TABLE 3:

Summary of shunting operations for patients with coccidioidomycosis-related hydrocephalus

ParameterValue (range or %)
shunt-treated patients44 (100%)
ventriculoperitoneal shunt*40 (91%)
ventriculoatrial shunt*4 (9%)
mean shunt setting (mm H2O)*88 (0–178)
valve type
 Certas15
 Hakim34
 Polaris1
 ProGAV10
 Strata18
patients with shunt failure22 (50%)
mean no. of revisions if shunt failed2.5 (1–8)
median time to shunt failure (mos)4.0 (0.5–168)
ventricular response
 full17 (41%)
 partial15 (37%)
 none9 (22%)

At last clinical follow-up.

For the 78 shunting operations in which the valve brand was known and in which the patient did not undergo perioperative revision (< 1 week of having the shunt implanted).

Fig. 1.
Fig. 1.

Preoperative (A) and postoperative (B) axial CT scans of a patient demonstrating complete ventricular response to shunting. Preoperative (C) and postoperative (D) axial CT scans of a patient with a partial ventricular response to shunting. This patient had a Certas valve set at a pressure of approximately 145 mm H2O; lower settings did not decrease ventricular size but led to symptomatic extraaxial fluid collections as partially visualized in D. Preoperative (E) and postoperative (F) axial CT scans of a patient demonstrating no significant response in ventricular dimensions to shunting. This patient had a Strata valve set at a pressure of approximately 100 mm H2O. Shunting resolved the transependymal flow observed on the preoperative imaging but did not alter the ventricular size.

Shunt Failure and Revisions

Of the 44 patients, 22 (50%) experienced shunt failure and underwent a total of 55 revision surgeries during clinical follow-up (Fig. 2). The mean number of revision surgeries required if a patient suffered shunt failure was 2.5 (range 1–8). Of the 55 revision surgeries performed, 8 perioperative revisions were performed within 1 week of a prior shunt operation for either distal catheter preperitoneal placement (n = 3) or immediate valve revisions for unexpected low-pressure hydrocephalus (n = 5); these revisions were not included in further analyses. The median time to shunt failure was 4.0 months after surgery (range 0.5–168 months). The most common reason for shunt failure outside this perioperative window (n = 47) was due to clogging of the proximal or distal catheter or clogging within the valve mechanism (n = 38, 81%). A trend was observed (p = 0.051) toward the initiation of intrathecal antifungal therapy if a patient had ever experienced shunt failure when failure was considered a binary variable. However, no statistically significant interaction was found between intrathecal therapy use and increasing number of shunt revisions when the number of failures was analyzed as a continuous variable (Student t-test, 2-tailed, mean difference 0.93, p = 0.154, 95% CI –2.23 –0.36). Valve brand was successfully assessed from the operative reports for 86 of the 99 procedures included in this series. We therefore removed unknown valve types (n = 13) and the above-mentioned perioperative revisions (n = 8) from our analysis of failure rate by valve brand, leaving 78 operations in which valve brand was known and follow-up data were available (Table 4). No statistically significant differences were seen between valve brands when analyzed for shunt failure rates.

Fig. 2.
Fig. 2.

Kaplan-Meier survival curve demonstrating shunt functionality (y axis) as a function of time (x axis) for the 91 shunt operations performed outside the perioperative window.

TABLE 4:

Summary of total valves implanted and rates of shunt failure per valve type*

ValveTotal No. Valves ImplantedNo. RevisionsFailure Rate
Certas15533%
Hakim341750%
Polaris100%
ProGAV10440%
Strata181161%

For the 78 shunting operations in which the valve brand was known and in which the patient did not undergo perioperative revision (< 1 week of having the shunt implanted).

Discussion

In the present study, we have reported our retrospective experience with, to our knowledge, the largest published series of patients with hydrocephalus due to coccidioidomycosis. As demonstrated in other series, not all patients are at equal risk for the development of disseminated coccidioidomycosis, CNS involvement, and subsequent hydrocephalus. The majority of our patients were young males, and African or Asian heritage was associated with a significantly increased risk of coccidioidomycosis-related hydrocephalus. Most patients were not immunocompromised. The risk of shunt failure was high, and fully half of all patients in our series required 1 or more shunt revisions during the follow-up period. The 9% mortality rate during follow-up demonstrates the severity of this often-fatal disease process despite the best medical therapies. Our data also affirm several anecdotal observations about coccidioidomycosis-related hydrocephalus and its treatment.

First, the most common cause of shunt failure seen (81%) was mechanical clogging of the drainage system. Coccidioidomycosis can lead to significant proteinaceous debris; considerable biofilms or focal abscesses have been observed on catheters or within valve tapping chambers at the time of shunt revision.3 Unfortunately, our data do not suggest a solution to improve shunt longevity, as we did not observe any differences among shunt valve brands. As almost all of our patients had ventriculoperitoneal shunts, our study was not appropriately powered to assess if other distal placement sites had a lower failure rate. Appropriate medical therapy with systemic antifungals is necessary in patients with hardware placed in a chronically infected space, and all of our patients were maintained on systemic antifungal medication. The role of intrathecal antifungals was not the focus of our study, and any benefit of intrathecal therapy on shunt failure rate may be masked by a selection bias whereby more severe cases receive intrathecal antifungals.

Second, despite low drainage pressures and adequate CSF diversion, many patients with coccidioidomycosis-related hydrocephalus experienced persistent ventriculomegaly after shunt surgery. The mechanism for this is not well elucidated, but it may include an alteration in the compliance of the ventricular wall or entire brain parenchyma due to infectious scarring or altered extraventricular CSF circulation. The clinical importance of this with regard to patient chronic headache or subtle cognitive function changes is unclear. However, it behooves the clinician treating patients with coccidioidomycosis-related hydrocephalus to assume that ventricular size does not necessarily indicate shunt failure or a functional shunt system.

The strengths of the current study include a relatively large number of patients with long follow-up (mean 63 months after shunt placement), and a serology- or culture-confirmed diagnosis of CNS coccidioidomycosis in all patients. Our study was retrospective in nature and suffers from the inherent limitations of any such study. The treating physician chose the valve brand and setting used, and this may have introduced undetected confounding variables. Similarly, our study spanned treatment over 2 decades, and valve brands and treatment algorithms may have shifted over this time period. There was no standardized follow-up for patients, and so those individuals with more severe disease and uncontrolled symptoms may have been more likely to continue to follow up with the neurosurgical and infectious disease services, resulting in selection bias. Some patients who were successfully treated with antifungals may have become shunt independent, and this would have gone undetected in our retrospective review. We are a tertiary referral center, and our patient disease severity may not reflect that seen within a community setting. We were not able to accurately assess patient compliance with oral antifungals in this retrospective review, and this certainly may contribute to shunt failure. Lastly, we purposely only included patients who underwent CSF diversion, so we could not assess the number of patients who were successfully treated with temporary external CSF drainage and medical therapy and did not undergo permanent shunting. Similarly, we did not include patients who may have been treated successfully with endoscopic third ventriculostomy; however, our anecdotal experience is that third ventriculostomy is rarely successful in the setting of coccidioidomycosis (presumably due to basilar cisternal arachnoid scarring). As CSF characteristics at the time of surgery, such as protein, glucose, lactate, or other measurable values, were not routinely obtained on all patients, these lab values were not included in our study. A prospective study that examines the relationships of these values with shunt outcomes or ventricular response would be worthwhile.

Conclusions

Hydrocephalus is a serious cause of morbidity and mortality in patients with CNS coccidioidomycosis. Patients of African and Asian descent are at higher risk for the disease process. Shunt failure rates are high, usually due to obstruction. Not all patients' ventriculomegaly resolves, even with low-normal draining pressures. Multidisciplinary teams of neurosurgeons and infectious disease specialists are required to treat these challenging patients.

Disclosure

The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

Author contributions to the study and manuscript preparation include the following. Conception and design: Nakaji, Hardesty, Beck, Gonzalez, Moran. Acquisition of data: Hardesty, Ramey, Afrasiabi, Beck. Analysis and interpretation of data: Hardesty, Ramey. Drafting the article: Hardesty. Critically revising the article: all authors. Reviewed submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: Nakaji. Statistical analysis: Hardesty. Administrative/technical/material support: Nakaji, Gonzalez. Study supervision: Nakaji.

References

  • 1

    Almoujahed MOJohnson LBGehring RKhatib R: Coccidioidal meningitis: incidental diagnosis 3 y after ventriculoperitoneal shunt placement for hydrocephalus. Scand J Infect Dis 34:1421432002

  • 2

    Dashti SRMcDougall CGToledo MMSpetzler RF: Clipping of a mycotic basilar trunk aneurysm under cardiac arrest in a pregnant AIDS patient. Skull Base 20:4594632010

  • 3

    Davis LECook GCosterton JW: Biofilm on ventriculo-peritoneal shunt tubing as a cause of treatment failure in coccidioidal meningitis. Emerg Infect Dis 8:3763792002

  • 4

    Drake KWAdam RD: Coccidioidal meningitis and brain abscesses: analysis of 71 cases at a referral center. Neurology 73:178017862009

  • 5

    Galgiani JNCatanzaro ACloud GAJohnson RHWilliams PLMirels LF: Comparison of oral fluconazole and itraconazole for progressive, nonmeningeal coccidioidomycosis. A randomized, double-blind trial. Ann Intern Med 133:6766862000

  • 6

    Kakarla UKKalani MYSharma GKSonntag VKHTheodore N: Surgical management of coccidioidomycosis of the spine. Clinical article. J Neurosurg Spine 15:4414462011

  • 7

    Mathisen GShelub ATruong JWigen C: Coccidioidal meningitis: clinical presentation and management in the fluconazole era. Medicine (Baltimore) 89:2512842010

  • 8

    Mendel EMilefchik ENAmadi JGruen P: Coccidioidomycosis brain abscess. Case report. J Neurosurg 81:6146161994

  • 9

    Romeo JHRice LBMcQuarrie IG: Hydrocephalus in coccidioidal meningitis: case report and review of the literature. Neurosurgery 47:7737772000

  • 10

    Wang CYJerng JSKo JCLin MFHsiao CHLee LN: Disseminated coccidioidomycosis. Emerg Infect Dis 11:1771792005

  • 11

    Winston DJKurtz TOFleischmann JMorgan DBatzdorf UStern WE: Successful treatment of spinal arachnoiditis due to coccidioidomycosis. Case report. J Neurosurg 59:3283311983

  • 12

    Wrobel CJMeyer SJohnson RHHesselink JR: MR findings in acute and chronic coccidioidomycosis meningitis. AJNR Am J Neuroradiol 13:124112451992

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Article Information

Address correspondence to: Peter Nakaji, M.D., Neuroscience Publications, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, 350 W. Thomas Rd., Phoenix, AZ 85013. email: neuropub@dignityhealth.org.

Please include this information when citing this paper: published online July 25, 2014; DOI: 10.3171/2014.6.JNS14111.

© AANS, except where prohibited by US copyright law.

Headings

Figures

  • View in gallery

    Preoperative (A) and postoperative (B) axial CT scans of a patient demonstrating complete ventricular response to shunting. Preoperative (C) and postoperative (D) axial CT scans of a patient with a partial ventricular response to shunting. This patient had a Certas valve set at a pressure of approximately 145 mm H2O; lower settings did not decrease ventricular size but led to symptomatic extraaxial fluid collections as partially visualized in D. Preoperative (E) and postoperative (F) axial CT scans of a patient demonstrating no significant response in ventricular dimensions to shunting. This patient had a Strata valve set at a pressure of approximately 100 mm H2O. Shunting resolved the transependymal flow observed on the preoperative imaging but did not alter the ventricular size.

  • View in gallery

    Kaplan-Meier survival curve demonstrating shunt functionality (y axis) as a function of time (x axis) for the 91 shunt operations performed outside the perioperative window.

References

1

Almoujahed MOJohnson LBGehring RKhatib R: Coccidioidal meningitis: incidental diagnosis 3 y after ventriculoperitoneal shunt placement for hydrocephalus. Scand J Infect Dis 34:1421432002

2

Dashti SRMcDougall CGToledo MMSpetzler RF: Clipping of a mycotic basilar trunk aneurysm under cardiac arrest in a pregnant AIDS patient. Skull Base 20:4594632010

3

Davis LECook GCosterton JW: Biofilm on ventriculo-peritoneal shunt tubing as a cause of treatment failure in coccidioidal meningitis. Emerg Infect Dis 8:3763792002

4

Drake KWAdam RD: Coccidioidal meningitis and brain abscesses: analysis of 71 cases at a referral center. Neurology 73:178017862009

5

Galgiani JNCatanzaro ACloud GAJohnson RHWilliams PLMirels LF: Comparison of oral fluconazole and itraconazole for progressive, nonmeningeal coccidioidomycosis. A randomized, double-blind trial. Ann Intern Med 133:6766862000

6

Kakarla UKKalani MYSharma GKSonntag VKHTheodore N: Surgical management of coccidioidomycosis of the spine. Clinical article. J Neurosurg Spine 15:4414462011

7

Mathisen GShelub ATruong JWigen C: Coccidioidal meningitis: clinical presentation and management in the fluconazole era. Medicine (Baltimore) 89:2512842010

8

Mendel EMilefchik ENAmadi JGruen P: Coccidioidomycosis brain abscess. Case report. J Neurosurg 81:6146161994

9

Romeo JHRice LBMcQuarrie IG: Hydrocephalus in coccidioidal meningitis: case report and review of the literature. Neurosurgery 47:7737772000

10

Wang CYJerng JSKo JCLin MFHsiao CHLee LN: Disseminated coccidioidomycosis. Emerg Infect Dis 11:1771792005

11

Winston DJKurtz TOFleischmann JMorgan DBatzdorf UStern WE: Successful treatment of spinal arachnoiditis due to coccidioidomycosis. Case report. J Neurosurg 59:3283311983

12

Wrobel CJMeyer SJohnson RHHesselink JR: MR findings in acute and chronic coccidioidomycosis meningitis. AJNR Am J Neuroradiol 13:124112451992

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