Coccidioidal meningitis

INTRODUCTION — Coccidioidomycosis is caused by the dimorphic fungi of the genus Coccidioides (C. immitis and C. posadasii), which are endemic in regions of the Southwestern United States as well as areas of Central and South America. Coccidioidomycosis has protean manifestations. One of the most severe is coccidioidal meningitis, a form of disseminated infection. As with other forms of extrathoracic disseminated coccidioidal infection, Coccidioides spp appear to spread hematogenously after an initial pulmonary infection and establish a tissue-destructive lesion in the meninges.

This topic will review the clinical manifestations, diagnosis, and treatment of coccidioidal meningitis. Primary pulmonary infection and other forms of disseminated infection are discussed elsewhere. (See "Primary pulmonary coccidioidal infection" and "Manifestations and treatment of nonmeningeal extrathoracic coccidioidomycosis" and "Management considerations, screening, and prevention of coccidioidomycosis in immunocompromised individuals and pregnant patients".)

EPIDEMIOLOGY — Coccidioidomycosis is caused by the dimorphic fungi of the genus Coccidioides [1]. It is now recognized as consisting of two species, C. immitis and C. posadasii [2-4]. However, their clinical manifestations, including their ability to cause meningitis, are similar. (See "Primary pulmonary coccidioidal infection", section on 'Microbiology'.)

Precise statistics about the incidence of coccidioidal meningitis are not available. The Arizona Department of Health Services (AZDHS) found that, in 2007, 8 percent of reported new coccidioidal infections were disseminated and, of those, 17 percent involved the central nervous system [5]. Applying these statistics to the total number of 7689 reported cases in Arizona (the mean number of annual cases reported to AZDHS from 2015 to 2019) provides an annual estimate of about 105 cases of coccidioidal meningitis in Arizona or 175 cases in the United States. Since it is estimated that there are more than 150,000 infections with Coccidioides species annually, these estimates suggest that the proportion of patients with meningitis is approximately 0.1 percent of all exposures.

CLINICAL MANIFESTATIONS — Meningitis is the most lethal complication of coccidioidomycosis, and thus it is crucial to recognize it. If untreated, coccidioidal meningitis results in death in 95 percent of patients within two years [6]. This contrasts sharply with other forms of coccidioidomycosis, which are either self-limited respiratory syndromes or cause chronic focal morbidity within or beyond the lungs (table 1). (See "Primary pulmonary coccidioidal infection" and "Manifestations and treatment of nonmeningeal extrathoracic coccidioidomycosis" and "Management considerations, screening, and prevention of coccidioidomycosis in immunocompromised individuals and pregnant patients".)

Signs and symptoms — Central nervous system infection usually occurs early in the course of infection, with symptoms developing within weeks to months after primary infection. However, on occasion, intervals as long as one to two years or even longer have been noted [6,7], particularly in patients who received antifungal therapy initially for primary coccidioidal pneumonia [8]. The onset of symptoms is often subacute or even chronic.

The most common symptom of coccidioidal meningitis is a persistent headache, which is present in approximately 75 percent of patients. However, about 20 percent of patients with primary pulmonary infection also complain of headache during their self-limited illness [9]. Thus, clinical judgment is required during early infection to select patients who would benefit from further evaluation of this symptom. Characteristics of headaches that might suggest meningitis in a patient known to have recently developed coccidioidal pneumonia include:

●Persistence of headache

●Progressive worsening of headache

●Unusual severity of the headache

●Associated nausea and vomiting

●Blurring of vision

●Changes in mental status

If the lumbar meninges are involved, patients may also complain of lumbosacral back pain.

Upon presentation with meningitis, there may be few or no symptoms associated with the primary respiratory infection, and radiographic examination of the chest is frequently unremarkable. By contrast, approximately half of patients with meningitis have other extrathoracic lesions resulting from hematogenous dissemination. (See "Manifestations and treatment of nonmeningeal extrathoracic coccidioidomycosis".)

Physical exam — Physical examination findings are frequently absent early in the course of coccidioidal meningitis. Tremulousness and an intention tremor are sometimes present. However, nuchal rigidity is rarely present, and the Kernig and Brudzinski signs of meningeal irritation are usually not elicited.

Papilledema, indicating increased intracranial pressure and the development of hydrocephalus, is frequent in children, but only an occasional presenting sign in adults [10,11]. Papilledema, as well as cranial nerve palsies (resulting from nerve entrapment by basilar meningitis) or evidence of cerebral infarction (resulting from arteritis), are generally observed later in the course of the disease [12]. Gait abnormalities and focal neurologic deficits are seen in a minority of cases [4].

Laboratory findings — Nonspecific laboratory abnormalities may include hyponatremia in association with the syndrome of inappropriate antidiuretic hormone [13]. (See "Pathophysiology and etiology of the syndrome of inappropriate antidiuretic hormone secretion (SIADH)".)

Lumbar cerebrospinal fluid (CSF) analysis in patients with coccidioidal meningitis usually demonstrates increased numbers of leukocytes, ranging from a few to several hundred cells. However, very large numbers of leukocytes in the CSF, such as occurs with bacterial meningitis, are distinctly unusual.

●The majority of cells are typically lymphocytic, but early in the infection, a significant percentage of these leukocytes may be polymorphonuclear leukocytes, similar to early aseptic meningitis of presumed viral origin. (See "Aseptic meningitis in adults".)

●Significant numbers of eosinophils may also occur, but this finding is not specific for coccidioidal meningitis [14,15]. (See "Eosinophilic meningitis".)

Depression of the CSF glucose (which is often profoundly low) and an elevation of the CSF protein are usually noted. Typically, protein concentrations range up to 250 mg/dL. If protein concentrations in the range of 1 to 3 grams are obtained, this suggests that the process has been complicated by obstruction to the normal flow of CSF and suggests the development of hydrocephalus. (See 'Management of increased intracranial pressure' below.)

Rarely, Coccidioides organisms may be seen on direct microscopic examination of the CSF; such a finding would be indicative of a high fungal burden of disease [4]. Culture of the CSF is positive for Coccidioides spp in the minority of cases.

Imaging findings — Computed tomography (CT) scanning or magnetic resonance imaging (MRI) can identify structural abnormalities in the brain, which are not specific for coccidioidal meningitis. Basilar leptomeningeal enhancement is common. Hydrocephalus and cerebral infarction may occur in some cases [16]. Hydrocephalus is the most common complication of coccidioidal meningitis, occurring in up to 30 to 50 percent of patients. Vasculitic infarctions are usually due to inflammation of small- and middle-sized blood vessels [12]. Spinal arachnoiditis, meningioma-like masses, and cerebral abscesses due to coccidioidomycosis also have been reported [4,17,18].

MRI enhanced with gadolinium has largely supplanted CT because of increased sensitivity, particularly in the setting of vasculitic complications [19]. MRI is also more sensitive than CT for leptomeningeal enhancement in the posterior fossa, and it provides detailed images of the Sylvian aqueduct and the fourth ventricle, which can become obstructed.

An uncommon but serious complication of coccidioidal meningitis is the development of a vertebral artery aneurysm. Patients with suggestive clinical features should undergo magnetic resonance angiography.

DIAGNOSIS — The signs and symptoms of coccidioidal meningitis are nonspecific and can be produced by a variety of other diseases. Because routine cerebrospinal fluid (CSF) and imaging abnormalities are nonspecific, positive CSF antibodies, the presence of coccidioidal antigen, and/or detection of the organism via culture or polymerase chain reaction (PCR) testing are required for diagnosis. (See 'Approach to diagnosis' below.)

Since the onset of symptoms is often subacute or even chronic, delays in diagnosis of weeks or even months after the onset of meningeal symptoms can sometimes occur. Diagnostic delays are likely to continue to occur unless the clinician considers the diagnosis of coccidioidal meningitis and specifically tests for it. (See "Primary pulmonary coccidioidal infection", section on 'Epidemiology'.)

Approach to diagnosis

Initial approach — When coccidioidal meningitis is suspected, clinicians should obtain coccidioidal serology tests. These are likely to be positive in all patients with coccidioidal meningitis [20]. If positive or if the diagnosis is considered otherwise likely, we next perform neuroimaging and obtain CSF fluid for analysis via a lumbar puncture (LP). CSF should be specifically analyzed for cell count, glucose, protein, as well as for specific tests for coccidioidomycosis (see below). Fluid obtained from the lateral ventricle, such as might occur at the time of a ventriculoperitoneal shunt placement, is often not as diagnostically sensitive as CSF obtained by lumbar or cisternal aspiration and should be avoided as the initial test.

Specific tests to evaluate for Coccidioides spp include:

●CSF antibodies (preferably by immunodiffusion or complement fixation for immunoglobulin G [IgG]) (see 'CSF antibody testing' below)

●Fungal culture (see 'Culture' below)

●PCR testing (see 'Polymerase chain reaction testing' below)

●CSF antigen (see 'CSF coccidioidal antigen levels' below)

It is reasonable to obtain neuroimaging prior to an LP, particularly in patients suspected of having increased intracranial pressure and/or central nervous system (CNS) mass lesions. We prefer magnetic resonance imaging (MRI) with and without gadolinium but CT with and without contrast may also be done. A detailed discussion on when to perform neuroimaging prior to LP is presented elsewhere. (See "Lumbar puncture: Technique, contraindications, and complications in adults".)

A definitive diagnosis of coccidioidal meningitis is supported by isolating Coccidioides species from CSF or other CNS specimens; however, most cases are presumptively diagnosed by identifying anticoccidioidal antibodies in the CSF [4] in association with a compatible clinical syndrome and CSF profile. Additional information about the different types of tests is found below. (See 'Specific diagnostic tests' below.)

Because focal neurologic complications may emerge during treatment, especially within the first two years, it is useful to perform MRI with and without gadolinium of the brain at baseline (if it was not performed prior to the LP). Imaging of the spinal cord at baseline is also warranted if the patient has back pain or spinous tenderness on physical examination or demonstrates gait disturbances or other lower extremity neurologic abnormalities. (See "Manifestations and treatment of nonmeningeal extrathoracic coccidioidomycosis", section on 'Diagnosis'.)

Recommendations regarding follow-up imaging are discussed below. (See 'Monitoring treatment response' below.)

Approach when initial evaluation is negative — Since the treatment of coccidioidal meningitis is lifelong, it is important to establish a specific diagnosis. In general, coccidioidal meningitis can be excluded if there is no CSF pleocytosis, the CSF glucose is normal, and CSF coccidioidal-specific tests are negative in a CSF sample collected prior to empiric antifungal treatment. (See 'Management' below.)

If the initial evaluation of a patient with suspected coccidioidal meningitis is not diagnostic, it is valuable to test for other possible causes, as indicated, and, if still no diagnosis is made, a follow-up LP with CSF analysis should be considered. (See "Approach to the patient with chronic meningitis", section on 'Diagnosis'.)

On rare occasions, brain biopsy or meningeal biopsy has proven useful when MRI with gadolinium enhancement has identified lesions that are amenable to a surgical approach. Histopathology may also be useful if there is another focus of disseminated disease, such as a cutaneous lesion in association with a clinical presentation of chronic meningitis. (See "Manifestations and treatment of nonmeningeal extrathoracic coccidioidomycosis", section on 'Diagnosis'.)

Specific diagnostic tests

Culture — Recovering Coccidioides species from CSF confirms the diagnosis, but the organism is only detected on culture in approximately 15 percent of patients during the initial evaluation. Culturing the sediment of large volumes of CSF improves the diagnostic sensitivity.

When sending a CSF culture, the clinician caring for the patient should alert the microbiology laboratory, since appropriate biocontainment procedures are needed. Exposure to Coccidioides spp in the laboratory setting can lead to infection of laboratory staff.

CSF antibody testing — Detection of complement-fixing (CF) IgG antibodies by immunodiffusion or by true complement fixation in the cerebrospinal fluid (CSF) is nearly as specific as recovery of the organism by culture. However, on occasion, low titers of coccidioidal antibodies may be found in patients with pulmonary or disseminated coccidioidomycosis without meningitis if the CSF is concentrated before testing [21]. In addition, CF antibodies to Coccidioides spp are not always detectable in early coccidioidal meningitis. (See "Coccidioidomycosis: Laboratory diagnosis and screening", section on 'Detection of anticoccidioidal antibodies'.)

Once the patient is stable, serial monitoring of the serum CF titer to Coccidioides spp can be used as a guide for management [4]. (See 'Monitoring treatment response' below.)

Other serologic tests may be performed on CSF but are less useful than the CF titer. As an example, antibodies detected by a commercially available enzyme-linked immunoassay may be indicative of coccidioidal meningitis, but their significance is not well established and their use in this circumstance is discouraged. (See "Coccidioidomycosis: Laboratory diagnosis and screening".)

CSF coccidioidal antigen levels — Measuring coccidioidal antigen concentrations in CSF specimens appears to improve the diagnostic yield of CSF analysis. The use of antigen testing was supported in a study from Arizona that included retrospective data from one medical center and prospective data from another [22]. In this study, CSF coccidioidal antigen testing was more frequently positive than antibody testing or culture and had a sensitivity of 93 percent and a specificity of 100 percent.

Polymerase chain reaction testing — Polymerase chain reaction (PCR) testing for Coccidioides spp may be useful in the CSF. However, while more rapid, PCR is likely no more sensitive than fungal culture of the CSF based on studies using bronchoalveolar lavage fluid [23].

MANAGEMENT — All patients with coccidioidal meningitis should receive antifungal treatment. If untreated, coccidioidal meningitis results in death in 95 percent of patients within two years [6]. Most patients who are treated with fluconazole survive, but lifelong therapy is necessary to prevent relapse [24,25]. (See 'Antifungal therapy' below.)

The treatment of coccidioidal meningitis has evolved to include oral therapies that have largely supplanted the need to instill antifungal agents directly into the cerebrospinal fluid (CSF). Nonetheless, the management of coccidioidal meningitis remains difficult and often requires the orchestration of several medical subspecialties to optimize the clinical response.

Antifungal therapy — Treatment guidelines for coccidioidomycosis were published by the Infectious Diseases Society of America in 2016 [26]. Our approach is generally consistent with these recommendations.

Initial therapy

●Oral fluconazole is the initial drug of choice for treatment of coccidioidal meningitis [24,26,27]. Guidelines suggest an initial dose of 400 to 1200 mg daily [26]. We generally favor a starting dose of 800 mg daily. A higher dose (eg, up to 1200 mg daily) can be considered for those who are severely ill, such as those requiring admission to an intensive care unit. Once the patient is clinically stable, the dose may be reduced to 800 mg daily. For patients who cannot tolerate oral therapy, intravenous fluconazole can be given at the same dose.

Data demonstrating the efficacy of fluconazole for the treatment of coccidioidal meningitis come from an open-label study in which 37 of 47 evaluable patients (79 percent) treated with fluconazole at a dose of 400 mg daily responded to treatment [27]. Response rates were similar for patients with and without previous therapy, for patients with and without HIV infection, and for patients with and without preexisting hydrocephalus. Patients were followed for a median of 38 months and remained on fluconazole during this time; most improvement occurred within four to eight months after starting therapy. Of 10 nonresponders, one received a shunt and was then managed successfully by reinstituting fluconazole at 400 mg per day. Six others were switched to a higher dose of fluconazole (800 mg per day), four appeared to improve, one failed, and one was lost to follow-up. Of the remaining nonresponders, two patients with AIDS died, and one was managed with intrathecal amphotericin B.

●Itraconazole (200 mg two to three times daily) is a reasonable alternative if fluconazole is not tolerated or is not available [26]. Itraconazole in doses of 200 mg orally twice or three times daily has been reported to be as effective as fluconazole [28]. However, patients receiving itraconazole require therapeutic drug monitoring to ensure adequate absorption, and there are more drug-drug interactions with itraconazole compared with fluconazole. (See "Pharmacology of azoles", section on 'Itraconazole' and "Pharmacology of azoles", section on 'Drug interactions'.)

●Intrathecal (IT) amphotericin B deoxycholate was the only established therapy for coccidioidal meningitis prior to the availability of triazole antifungals. It is recommended as initial therapy only in pregnant females with coccidioidal meningitis during the first trimester of pregnancy because of the potential teratogenic effects of triazole antifungals on fetal development [1,29,30]. (See "Management considerations, screening, and prevention of coccidioidomycosis in immunocompromised individuals and pregnant patients", section on 'Pregnant patients' and 'Patients without a satisfactory response to initial therapy' below.)

There is no evidence that echinocandins are useful in the treatment of coccidioidal meningitis [1]. In addition, although intravenous liposomal amphotericin B (Ambisome) and amphotericin B lipid complex (Abelcet) have been shown to be beneficial in animal studies of coccidioidal meningitis [31-33] and in some case reports [34,35], their clinical utility has not yet been fully established in humans.

Maintenance therapy — Patients who respond to azole therapy should continue this treatment for life, because relapses upon discontinuing treatment are common and potentially fatal [24,25]. The maintenance dose of fluconazole remains unclear. Some experts continue fluconazole at 800 mg daily, while others, following prolonged treatment of at least one year at 800 mg daily, may reduce the dose to 400 mg daily. For those who were treated with itraconazole for coccidioidal meningitis, it is appropriate to continue it as maintenance therapy; the maintenance dose is 200 mg two to three times per day (depending upon their initial dose), and should be adjusted based on serum levels. (See "Pharmacology of azoles", section on 'Itraconazole'.)

Patient adherence can be problematic over time, and lack of medication adherence can lead to serious consequences. Thus, patients must be continually reminded about the need for lifelong therapy.

A more detailed discussion of how to monitor the response to treatment is found below. (See 'Monitoring treatment response' below.)

Management of increased intracranial pressure — Patients with increased intracranial pressure at the time of diagnosis can be managed initially with antifungal therapy and repeated lumbar punctures (LPs) [26]. However, most patients who develop hydrocephalus require a shunt for decompression [36]. Hydrocephalus may develop despite appropriate antifungal therapy and does not in itself dictate changing to another antifungal agent.

Shunts can be associated with a variety of complications; patients can develop recurrent distal obstruction, interventricular foraminal obstruction, and shunt failure. Recurrence of headache, nausea, vomiting, gait disturbance, or mental status changes should lead to prompt imaging of the brain. Patients with shunt malfunction can have the revision performed in a single procedure. However, when the shunt has developed a bacterial or other superinfection, the shunt should be removed and replaced during a second procedure [26]. (See "Infections of cerebrospinal fluid shunts".)

Monitoring treatment response — Patients should be monitored clinically and with laboratory testing to monitor the response to treatment.

●Once antifungal therapy is initiated, the response to therapy will usually first be noted by improvement of symptoms. This is frequently gradual and may take several weeks before objective improvement occurs. However, patients often note subjective improvement earlier.

●Serial monitoring of the serum complement-fixation titer to Coccidioides spp is an important adjunct to clinical assessment in gauging the response to treatment. This should be performed every 12 weeks. We typically expect titers to improve after 12 months, but this is variable. After the patient has demonstrated medication adherence and clinical and serologic improvement, patients can be monitored every 6 to 12 months. (See 'CSF antibody testing' above.)

●The role of repeat LP depends upon the patient’s response to therapy. In general, we do not repeat LP with CSF analysis in patients who are improved and clinically stable. However, for those patients with persistent or worsening symptoms or increasing serum coccidioidal titers, repeat LP with CSF analysis can be helpful. Increasing CSF pleocytosis, persistently low CSF glucose, and persistent CSF antibody response suggest lack of response.

With treatment, the CSF leukocytosis generally improves, although low numbers of leukocytes often persist for many months or even years in patients who otherwise appear to be doing well. Normalization of the CSF glucose seems to more reliably reflect clinical improvement. Patients who have persistent hydrocephalus often continue to have CSF abnormalities, especially elevated leukocyte counts, despite therapy [4].

●We do not repeat magnetic resonance imaging of the brain and/or spinal cord in patients who had abnormal findings at baseline if the patient is doing well. By contrast, imaging should be repeated in patients with a poor response to therapy.

Patients without a satisfactory response to initial therapy — Certain patients do not have a satisfactory response to initial treatment on follow-up. (See 'Monitoring treatment response' above.)

●Patients who are neurologically stable – For neurologically stable patients who clinically fail initial therapy with 800 mg daily of fluconazole, we change to an alternative orally administered triazole antifungal (eg, itraconazole, voriconazole, or delayed-release posaconazole). Isavuconazonium may also be considered based on limited data in coccidioidal meningitis [37]. Some experts prefer to increase the dose of fluconazole to 1200 mg daily rather than use one of these alternative agents, but we find many patients cannot tolerate high-dose fluconazole and we rarely see a clinical response. (See "Pharmacology of azoles", section on 'Fluconazole'.)

There are several case reports that describe patients with coccidioidal meningitis who progressed while receiving fluconazole and subsequently improved during treatment with voriconazole [38-40]. Other similar but unpublished anecdotal experiences have accumulated at referral centers [4]. The usual dosing of voriconazole is 400 mg orally twice daily for two doses, followed by 200 mg orally twice daily. Voriconazole doses as high as 400 mg orally twice daily have been required as salvage therapy in some patients who had disease progression while taking fluconazole.

However, voriconazole may be less well tolerated and produce more untoward reactions than fluconazole, most notably visual disturbances and dermal photosensitivity. We monitor serum voriconazole trough concentrations in all patients receiving voriconazole for coccidioidal meningitis in order to ensure that adequate concentrations are achieved and to prevent toxicity from high concentrations. Although there are no guidelines for target voriconazole concentrations, we check a trough concentration one week into therapy with a goal range of >1 to 2 mcg/mL and <5.5 mcg/mL [41]. (See "Pharmacology of azoles", section on 'Voriconazole'.)

Case reports also describe patients with coccidioidal meningitis who were refractory to initial antifungal therapy with fluconazole but who improved during treatment with posaconazole [40,42]. Thus, as with voriconazole, posaconazole might also be considered as alternative therapy in selected patients.

The usual dosing of posaconazole delayed-release tablets (delayed-release posaconazole) is 300 mg orally twice daily on the first day, then 300 mg once daily thereafter, taken with food. Trough concentrations should be obtained after seven days of therapy, and, based on experience, we prefer levels between 1000 and 4000 ng/mL. Some reports have described a mineralocorticoid-excess syndrome consisting of hypertension and hypokalemia in patients receiving posaconazole [43]. In such cases, levels are frequently elevated (>3000 ng/mL), and the dose of delayed-released posaconazole should be lowered or discontinued and an alternative found. (See "Pharmacology of azoles", section on 'Posaconazole'.)

A discussion of itraconazole for the treatment of coccidioidal meningitis is discussed above. (See 'Initial therapy' above.)

●Patients with worsening neurologic status – For patients with persistent lumbar fluid pleocytosis and worsening neurologic symptoms or signs, IT amphotericin B deoxycholate should be initiated, with or without continuing azole treatment [44]. Because of its toxicity and difficulty of administration, IT amphotericin B therapy should be managed only by clinicians experienced with this therapy.

The dose of IT amphotericin B deoxycholate normally ranges between 0.01 mg and 1.5 mg per dose administered at intervals ranging from daily to weekly, beginning at a low dose and increasing the dose until patient intolerance appears. It can be instilled by direct injection into the lumbar and cisternal spaces or through lumbar, cisternal or ventricular reservoirs [44]. Except for the latter approach, all require considerable expertise [45] and should not be attempted without experience. Complications of IT amphotericin B include headache, nausea and vomiting, arachnoiditis, bleeding, secondary infection, and neurotoxicity, including ophthalmoplegia, hearing loss, and ataxia [44]. While intraventricular installation through an Ommaya reservoir is the most commonly employed method, it may not be as effective as other routes if noncommunicating hydrocephalus is present. When instilling through the lumbar route, hyperbaric solutions and Trendelenburg positioning have been employed [46,47]. Newer lipid formulations of amphotericin B are generally not used for IT administration. (See "Pharmacology of amphotericin B", section on 'Intrathecal'.)

COMPLICATIONS — Vasculitis complicated by stroke has become increasingly recognized as a complication of coccidioidal meningitis. Other than continuing antifungal therapy, the optimal management is not clear [48]. However, a retrospective study found that adjunctive corticosteroids given after the first event was associated with a reduction in future strokes [49].

Other complications of coccidioidal meningitis include adhesive arachnoiditis and development of a spinal cord syrinx. While fortunately rare, there are no clear therapies to manage these.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Coccidioidomycosis".)

SUMMARY AND RECOMMENDATIONS

●General principles – Coccidioidomycosis is caused by the dimorphic fungi of the genus Coccidioides (C. immitis and C. posadasii), which are endemic in desert regions of the Southwestern United States and Central and South America. Coccidioidomycosis has protean manifestations. One of the most severe is coccidioidal meningitis, a form of disseminated infection. (See 'Introduction' above.)

●Clinical manifestations – The most common symptom of coccidioidal meningitis is persistent headache, which is present in approximately 75 percent of patients. The onset of symptoms is often subacute or even chronic. Cerebrospinal fluid (CSF) usually reveals a lymphocytic pleocytosis with elevated protein and low glucose concentrations. If untreated, meningitis results in death in 95 percent of patients within two years. This contrasts sharply with most nonmeningeal infections. (See 'Clinical manifestations' above.)

●Diagnosis

•The diagnosis of coccidioidal meningitis is often delayed by weeks or even months after the onset of meningeal symptoms because the symptoms and signs of coccidioidal meningitis are nonspecific and can be produced by a variety of other diseases. (See 'Diagnosis' above.)

•When coccidioidal meningitis is suspected, we perform a lumbar puncture and send CSF for routine studies as well as specific tests for Coccidioides species (CSF antibodies, fungal culture, CSF antigen, polymerase chain reaction testing). A definitive diagnosis of coccidioidal meningitis is supported by isolating Coccidioides species from CSF or other central nervous system specimens; however, most cases are presumptively diagnosed by identifying anticoccidioidal antibodies in the CSF. (See 'Approach to diagnosis' above and 'Specific diagnostic tests' above.)

●Management

•Initial therapy – For most patients with coccidioidal meningitis, we suggest treatment with oral fluconazole (Grade 2C). We generally favor an initial dose of 800 mg daily, but a higher dose (1200 mg daily) can be considered temporarily for those who are severely ill. Itraconazole is a reasonable alternative if fluconazole is not tolerated or available. Azoles are contraindicated during the first trimester of pregnancy given the risk of teratogenicity; in such patients, treatment typically involves intrathecal amphotericin B. (See 'Initial therapy' above.)

•Maintenance therapy – Patients should continue treatment for life because relapses upon discontinuing treatment are common and potentially fatal. The dose of fluconazole in this setting remains unclear. Some experts continue fluconazole at 800 mg daily, while others may reduce the dose to 400 mg daily after a prolonged period of time (eg, more than one year). (See 'Maintenance therapy' above.)

•Management of increased intracranial pressure – Development of hydrocephalus may occur despite antifungal therapy and does not in itself dictate switching to an alternative agent. However, patients who develop hydrocephalus nearly always require a shunt for decompression. (See 'Management of increased intracranial pressure' above.)

•Monitoring – Patients should be monitored clinically and with laboratory testing to assess the response to treatment. Response to antifungal therapy is gradual and may take several weeks before objective improvement occurs. (See 'Monitoring treatment response' above.)

•Refractory infection – For patients who do not respond to initial therapy with fluconazole at a dose of 800 mg daily, we change to an alternative orally administered triazole antifungal (eg, itraconazole, voriconazole, or delayed-release posaconazole); however, some experts prefer to increase the dose of fluconazole to 1200 mg daily rather than use one of these alternative agents. Patients with worsening neurologic symptoms and signs are also candidates for intrathecal amphotericin B therapy, but this should only be administered by someone skilled in this procedure. (See 'Patients without a satisfactory response to initial therapy' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges John Galgiani, MD, who contributed to an earlier version of this topic review.