Coccidioidomycosis: neurologic manifestations …

Arielle P Davis MD

Infectious Disorders

Updated 06.10.2024
Released 02.28.2005
Expires For CME 06.10.2027

Coccidioidomycosis: neurologic manifestations

Author: Arielle P Davis MD

See Contributor Disclosures

Editor: Christina M Marra MD

Coccidioidomycosis: neurologic manifestations

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Introduction

Overview

Coccidioidomycosis is a common fungal infection in the southwestern United States of America and other Central and South American nations. Only a few patients who acquire primary coccidioidomycosis develop neurologic complications. Importantly, these patients are identified by their travel through endemic areas and often present elsewhere. In this article, the author reviews the clinical manifestations, diagnostic approach, and management of neurologic manifestations of coccidioidomycosis.

Key points

	• Coccidioidomycosis is an endemic fungal infection, so a comprehensive travel history is essential.
	• Coccidioidomycosis should be considered in the differential diagnosis of patients with meningitis, particularly those with more subacute clinical presentations.

Historical note and terminology

The first prehistoric human infection with Coccidioides immitis was reported in an ancient Indian skeleton from Arizona, dating to 1000 to 1400 AD (51).

In 1892 the first modern case of coccidioidomycosis was reported in an Argentine soldier. He developed progressive, verrucous skin lesions of the face that resembled mycosis fungoides and that contained spherical nonmotile organisms with a highly refractile double wall (93). Four years later, the same organism was isolated from similar papulonecrotic skin lesions in two immigrants to California (99). The organism was initially incorrectly identified as a protozoan and named Coccidioides because it resembled a Coccidia (a protozoa and intracellular parasite). The current term Coccidioides immitis was coined when immitis (not mild) was added to the name to indicate its virulence (99). In 1900, Ophuls recognized the true nature of the organism as a dimorphic fungus and not a protozoan (85). Five years later, he described the first case of coccidioidal meningitis in an autopsy of a patient with widely disseminated disease (84). The first case of meningitis as the sole site of extrapulmonary involvement was reported in 1924 (79). An autopsy series of 14 patients was published in 1936 that included CSF findings in coccidioidal meningitis (02). In the following year, the cause of “Valley fever” in California’s San Joaquin Valley was confirmed as coccidioidomycosis (31). The epidemiological scale of this disease in the San Joaquin Valley was revealed in 1946 by using a newly developed skin test and serological antigen (coccidioidin) (108). In 2002, Coccidioides posadasii, formerly known as non-Californian Coccidioides immitis, was isolated as a distinct species with numerous varying DNA polymorphisms, but clinically both species present with the same spectrum of disease (41).

Clinical manifestations

Presentation and course

	• Coccidioidomycosis should be considered in the differential for patients living in or with travel to endemic areas. In the United States, most cases are identified in California and Arizona.
	• Coccidioidal meningitis is the most common extrapulmonary neurologic manifestation, presenting with headache, altered mental status, and nausea and vomiting.
	• Hydrocephalus and central nervous system vasculitis are important complications of coccidioidal meningitis.

Primary infection with C immitis and C posadasii, soil-dwelling fungi endemic most commonly in the desert of the southwestern United States, is through inhalation. Approximately 60% of those infected with C immitis are asymptomatic; the only evidence of such infections is usually a positive serology. The remaining 40% of patients develop an influenza-like illness, usually 1 to 4 weeks after exposure. This is characterized by fever, drenching night sweats, headaches, malaise, anorexia, rash (erythema multiforme or erythema nodosum), arthralgias (commonly symmetric in distal lower extremities), myalgia, cough, and pleuritic chest pain (35; 36). Fatigue (84%), cough (67%), dyspnea (59%), and fever (54%) were the most reported symptoms in an enhanced surveillance study of newly identified coccidioidomycosis in Arizona (125). Abnormal chest radiographs are found in about half the symptomatic patients. Typically, lung infiltrates are associated with hilar adenopathy, although other patterns are possible (21). Pleural effusions occur as well. Most symptoms resolve in 2 to 3 weeks except for fatigue that not infrequently lingers for weeks to months. The median symptom duration in the Arizona enhanced surveillance study was 120 days, although the study did not detail which symptoms persisted (125).

About 5% of the patients who have pneumonia during the primary infection develop pulmonary nodules, and another 5% have cavitary lesions. A small proportion of patients have a diffuse pneumonia that clinically and radiologically is indistinguishable from acute respiratory distress syndrome (21).

Extrapulmonary (disseminated) disease. Disseminated disease occurring outside the lungs and pleural space occurs in 0.5% to 2% of those with coccidioidomycosis (27).

Extrapulmonary disease typically occurs within weeks to several months after exposure, but the incubation period can be longer in the setting of immunosuppression or prior antifungal therapy for pulmonary infection with relapse several years after initial infection (28).

The nonneurologic extrapulmonary manifestations commonly include the skin (papules, verrucous lesions, plaques, chronic ulceration, superficial abscesses, pustules, granulomatous lesions), bone (osteomyelitis, commonly involving bones of the vertebrae, tibia, skull, metacarpals, femur, metatarsals, and ribs), and joints. Other affected tissues are the eye, larynx, thyroid, endocardium, peritoneal cavity, prostate, kidney, and uterus.

About one third of coccidioidal extrapulmonary lesions involve the central nervous system, with chronic granulomatous meningitis being the most common.

Neurologic manifestations of coccidioidomycosis. Neurologic complications of coccidioidomycosis occur in approximately 200 patients annually in the United States. Entry into the CNS usually occurs within a few months of the primary pulmonary infection (17). One natural history study found that although most of those with CNS dissemination presented within 6 months of primary infection, up to 22% occurred after 1 year (12).

The neurologic syndromes are divisible into the following categories:

(1) Leptomeningitis
(2) Meningoencephalitis
(3) Parenchymal granulomas and abscesses with or without meningitis
(4) Vasculitis usually in association with meningitis
(5) Complications of meningitis (including hydrocephalus)
(6) Spinal cord involvement
(7) Cranial and vertebral osteomyelitis with associated neurologic complications.

Leptomeningitis. This is the most common CNS manifestation and presents as a chronic granulomatous meningitis, mainly involving the basal meninges. Most of the other CNS complications develop in association with meningitis. Dissemination to the meninges occurs early in the natural history of the disease (135) and rarely manifests later than 2 years after the initial infection (39). On one occasion, however, clinical manifestations remained latent for 12 years (40). The onset of symptoms is typically subacute and sometimes coincides with the pulmonary symptoms but usually appears several months after exposure and infrequently thereafter.

Coccidioidal meningitis affects people of all ages. The male-to-female ratio is 4:1.

Non-Caucasians are more likely to develop coccidioidal meningitis than Caucasians, with one series showing elevated risk highest in those of African descent (34). A history of residence or travel to an endemic area is a consistent factor in acquiring the disease; coccidioidomycosis should be considered in a patient with meningitis suggestive of tuberculosis who has traveled to endemic zones (19).

Diabetes mellitus is associated with an increased risk of disseminated coccidioidomycosis (100). Pregnancy is also associated with a significantly higher risk of dissemination. In a study of 65 patients with coccidioidomycosis in pregnancy, 37 had disseminated disease and 29 died (126). Nonetheless, coccidioidomycosis is not transmitted to the fetus, but neonates can acquire infection secondary to aspiration of infected amniotic fluid or vaginal secretions at birth (24; 40). Involvement of the face by Coccidioides is suggested to pose a higher risk for meningitis than skin involvement in other areas of the body (07).

Although cell-mediated immune suppression is likely an important risk factor for meningitis, only 2% of cases have had immunosuppressive therapy or are people living with HIV (PLWH) prior to development of coccidioidal meningitis (18). Genetic susceptibility probably plays a subtle but important role in the risk of meningitis as well (48).

According to an analysis of 31 patients with meningitis by Bouza and colleagues and another 114 patients from the literature, the most common symptoms are fever (88%), headache (97%), nausea and vomiting (92%), weight loss (75%), and altered mental status (96%). Other clinical features include nuchal rigidity (55%), diplopia, papilledema (80%), other cranial neuropathies, focal neurologic signs (71%), personality changes (86%), and seizures (86%) (17). A single center retrospective study of 133 patients with coccidioidal meningitis found similar high rates of headache (85%), but lower rates of encephalopathy (55%) and fever (50%) (107). Many patients with coccidioidal meningitis also have extra neurologic manifestations. These include skin lesions, subcutaneous abscesses, and pulmonary symptoms that assist in recognizing the etiology of this meningitis (17). Sivasubramanian and colleagues identified coexisting pulmonary (41%), cutaneous (5%), and osseous (1.5%) involvement (107).

Before the advent of antifungal treatment, long-term survival was better in patients with coccidioidal meningitis as the sole site of extrapulmonary dissemination compared to those with multiple organ involvement and meningitis (127). Nonetheless, coccidioidal meningitis is associated with significant mortality and morbidity, with overall age-adjusted mortality rate of 0.59 per 1 million person-years (15; 54). Even in a more modern series of coccidioidal meningitis from 2010 to 2020, 23% of patients died related to complications of the disease (107).

Meningoencephalitis. Meningoencephalitis is the term employed when the parenchyma of the brain is clinically affected in patients with leptomeningitis. In many patients, diffuse encephalitis is observed pathologically in addition to meningitis (132; 78).

Parenchymal granulomas and abscesses with or without meningitis. The encephalitis found in most patients with coccidioidomycosis meningitis results from an extension of the inflammatory process in the subarachnoid space along Virchow-Robin spaces, across the pia mater, and into the underlying parenchyma. In a study, 25 of 32 (78%) patients with coccidioidal meningitis showed evidence of encephalitis (109). Twelve of these patients also had a necrotizing myelitis.

The first coccidioidal parenchymal lesion was described in 1928. The patient had disseminated disease without meningitis and a 4 mm caseous area within the “right optic thalamus” (56). Since then, at least 39 cases of parenchymal lesions of the brain have been reported in the literature; one third of them had no evidence of meningitis (10). The pathological processes were variously described as caseous lesions, abscesses, miliary granulomas, and masses involving mainly the cerebellum and cerebral hemispheres. Diabetes mellitus was noted in many cases. Clinically, these patients presented with symptoms and signs of meningitis, seizures, and focal neurologic deficits.

Focal neurologic deficits can develop secondary to embolization from coccidioidal endocarditis; these embolic lesions sometimes develop into abscesses (98).

CNS vasculitis. Vasculitis consists of an inflammatory reaction involving the walls of small- and medium-sized vessels within the subarachnoid space. Associated parenchymal necrosis occurs from thrombosis in the affected vessel (endarteritis obliterans). As a result, patients often deteriorate due to sudden, focal neurologic deficits. Complications from vasculitis are common and occur in 52% of patients with fatal coccidioidal meningitis (109). Additionally, 9% to 40% of the patients with nonfatal coccidioidal meningitis have white matter lesions consistent with vasculitis-associated infarctions on computed tomography (CT) or magnetic resonance (MR) scans (103; 38). Infarctions of the spinal cord are frequently found at autopsy as well (109). Rarely, intracranial vasospasm can occur secondary to vasculitis or subacute fibrotic changes (53).

Spinal cord involvement. Involvement of the spinal cord or its roots in the cauda equina usually occurs in the setting of chronic meningitis. The mechanisms include compression from a fibrotic or exudative meningeal reaction, abscess formation, adhesive arachnoiditis, or infarction from endarteritis obliterans involving the arteries supplying the spinal cord.

There are several cases in the literature describing primarily intramedullary spinal cord abscesses, with varying clinical presentations depending on location of lesion, but at worst these have included rapidly progressive quadriparesis (65; 118; 08).

Vertebral osteomyelitis may develop in the setting of coccidioidomycosis, with the most common presenting symptoms being motor and/or sensory deficit in 60% and back pain in 55%. In a review of 20 patients with vertebral osteomyelitis due to coccidioidomycosis, an average of 4.3 vertebral levels were involved, pathologic fractures were seen in 65%, cord compression in 45%, and an epidural collection in 45% (102).

Additional complications.

Hydrocephalus. This is the most common complication of coccidioidal meningitis and occurs in 40% to 100% of the patients with coccidioidal meningitis (17; 137; 43; 107). Raised intracranial pressure results from obstruction of spinal fluid flow in the subarachnoid space, producing communicating hydrocephalus, or in the ventricular cavity, resulting in noncommunicating hydrocephalus. This may be a presenting manifestation or a late complication. Most patients with late-onset hydrocephalus continue to have CSF evidence of active disease despite treatment (57). In coccidioidomycosis-related hydrocephalus, patients typically have prolonged hospitalizations, increased mortality, normal to low pressure setting requirements for CSF drainage, and high shunt failure rates, with an average of 2.6 revisions. Higher shunt failure rates are seen with an antisiphon device (80). Sivasubramanian and colleagues corroborated the high shunt failure rate, with 53% of the 80 patients with coccidioidal meningitis requiring a shunt revision, with an average of 2.6 revisions needed (107). There are also rare cases of fourth ventricle isolation in the setting of recurring shunt infections or chronic shunting of the lateral ventricles (66).

Mycotic aneurysms. A solitary case report described a young woman with coccidioidal meningitis who presented with subarachnoid hemorrhage secondary to multiple mycotic aneurysms (49). Fungal aneurysms tend to occur in the more proximal parts of the intracranial vessels as compared to bacterial aneurysms that usually involve the more peripheral cerebral vasculature, for example, beyond the branch points of the middle cerebral artery in the Sylvian fissure.

Cerebral venous thrombosis. A solitary case of coccidioidal meningitis with massive dural and cerebral venous thrombosis in the setting of AIDS was reported in 2000 (62).

Cranial and vertebral osteomyelitis. Osteomyelitis produces neurologic symptoms from compression of the spinal cord or its nerve roots or spread of infection from the epidural space along venous channels into the spinal cord (82; 136). Another pattern of involvement is invasion of the disk space that is accompanied by heterogeneous destruction of bone marrow in adjacent vertebrae and infiltration of extra osseous soft tissue. Clinical findings include vertebral and radicular pain, kyphosis, sensory loss, and paraparesis.

Guillain-Barré syndrome. This syndrome was reported in an immunocompromised patient 5 weeks following the development of pneumonia due to coccidioidomycosis (81). This is the first known report of an association between coccidioidomycosis infection and Guillain-Barré syndrome. It was hypothesized that the lowering of the patient’s typical tacrolimus dose to avoid a drug interaction with fluconazole allowed the patient to then mount an immune response that led to Guillain-Barré syndrome.

Clinical vignette

A 40-year-old Hispanic male presented with a 3-month history of fever, malaise, night sweats, headaches, diplopia, and weight loss. He previously worked in Tucson, Arizona for 1 year and moved to Missouri 2 months prior to the onset of symptoms. Neurologic examination revealed a right lateral rectus palsy and nuchal rigidity.

A chest x-ray disclosed a right upper lobe infiltrate. CT scan of the head showed mild hydrocephalus with fourth ventricular dilatation and diffuse basal meningeal enhancement. MRI of the brain revealed similar findings.

In view of his residence in Arizona, a diagnosis of coccidioidal meningitis was considered likely. Lumbar puncture found an opening pressure of 280 mm of water. CSF examination showed 585 white cells/mm3 with 8% eosinophils and 92% lymphocytes, glucose of 40 mg/dl, and protein of 200 mg/dl. Complement–fixing antibody titers to Coccidioides species were 1:16 in the serum and 1:8 in the CSF, establishing a serologic diagnosis of coccidioidal meningitis. A skeletal survey was obtained but failed to disclose additional coccidioidal lesions.

The patient was started on oral fluconazole, 400 mg/day. Gradually, over the next several weeks, the malaise, fever, night sweats, headaches, and nuchal rigidity abated. The right lateral rectus paresis slowly recovered over 3 months. A repeat MRI study showed some resolution of the hydrocephalus and diminished basal meningeal enhancement. Repeat CSF studies over 12 months marked a decline of the pleocytosis to 12 lymphocytes/mm3 and normalization of the glucose and protein. The last complement fixation antibody titers were 1:2 in both serum and CSF. A final chest x-ray showed complete resolution of the right upper lobe infiltrate.

At most recent follow-up, the patient was asymptomatic and continued to take oral fluconazole, 400 mg a day, which he will continue for his lifetime.

Biological basis

Etiology and pathogenesis

• Coccidioides species live as a mold in desert soil in endemic areas, and inhaling airborne fungal spores leads to infection.

In the central valley of California coccidioidomycosis is mainly caused by Coccidioides immitis, a dimorphic fungus that grows as a mold in soil inhabited by rodents (11). Coccidioides immitis has also been identified as a rare pathogen in Washington state (68; 83). However, in the remaining areas of the United States (California outside the central valley, New Mexico, Arizona, Texas, Utah, Nevada), Mexico, and other endemic areas in Central and South America, another species, Coccidioides posadasii (named after Posadas, the author of the first report of coccidioidomycosis 1892) is the causal organism (41). The two species can be differentiated by the length of microsatellite-containing loci and mutations in genes encoding fungal enzymes; however, they are indistinguishable in their colony characteristics and clinical manifestations.

The growth of Coccidioides occurs in two phases: the mycelial-arthrospore or mold phase in the soil (saprobic or environmental phase) and the spherule-endospore phase (parasitic or tissue phase) in infected tissues. In the soil, the mycelial or mold form develops branching, septate hyphae from which conidia (spores), called arthroconidia, form along its length. As arthroconidia mature, they become stable and are viable for long periods. In this form they are easily airborne, making them an ideal respiratory pathogen.

On inhalation, arthroconidia transform themselves into thick-walled spherules filled with endospores. Once the spherule matures, endospores are released, and each of the endospores starts the development of a new spherule. Thus, the infection is extended by repeated growth and continuation of its cycle. The Coccidioides mycelial form has different, secreted proteolytic enzymes that could be advantageous for the adaptation of Coccidioides to distinct environments during its complex life cycle (67). Coccidioidomycosis is not transmitted from person to person, and, therefore, no isolation procedures are required for hospitalized patients.

A host’s immune response to infection by Coccidioides involves an innate immune response as well as adaptive T helper subtype 1 (Th1) and Th17 responses (32). The tissue response is granulomatous, suppurative, or a combination of the two (55). If the Th1 response is less than robust and the predominant cell response is the less effective T helper subtype 2 (Th2), the resolution of infection is incomplete and leads to dissemination. This situation tends to occur in pregnancy (130) and with steroid treatment or immunosuppression.

Epidemiology

	• The incidence of coccidioidomycosis has been increasing, particularly in endemic Arizona and California.
	• Groups at risk for disseminated disease include those with depressed cellular immunity, such as those with poorly controlled HIV or immunosuppressive or immunomodulatory therapy, and pregnant women in their third trimester or postpartum.

Endemic areas. Coccidioidomycosis is endemic in the Western Hemisphere between the 40-degree latitudes north and south. The Lower Sonoran Life Zone regions, which have hot summer months, few winter freezes, rainfall between 5 and 20 inches a year, and alkaline soil, are particularly affected (43; 23). In the United States, this zone is found in the southwest, primarily in parts of California, Arizona, Nevada, New Mexico, and Texas. The southern San Joaquin Valley of California and southern Arizona have the highest endemicity. Other endemic areas include northern Mexico and some parts of Central and South America (87).

Importantly, frequent travel into and out of these areas requires physicians to recognize the occurrence of coccidioidomycosis outside the natural geographic boundaries of the organism (86; 90). This is particularly important for extrapulmonary manifestations of the disease and especially for meningitis that usually appears after a delay of a few weeks to months following the primary infection. Isolated cases of coccidioidomycosis have been reported from other parts of the world, but most of these reports occurred in persons with a history of travel to or contact with fomites from endemic areas (17; 90). Rapid population growth in the southwestern United States in recent decades and the increase in tourism may mean more individuals with coccidioidomycosis (89).

Although historically endemic areas tend to have higher case incidence, the endemic mycoses, including coccidioidomycosis, are expanding their boundaries and are no longer “endemic” to only certain locations. A study using Medicare claims data in the United States from 2007 to 2016 found that at least one county in 69% (35 out of 51) states, including Washington, DC, had an incidence of more than 100 cases per 100,000 person-years (72).

Prevalence and incidence. Infection occurs in 2% to 4% of the healthy population annually (11). An estimated 150,000 infections occur annually in the United States, with 10,000 to 20,000 diagnosed and reported, 600 to 1000 with disseminated disease, with an estimated 200 of these disseminated cases having neurologic involvement, and 160 deaths (54; 44). Human infection follows inhalation of arthroconidia. These spores become airborne by ground-disturbing activities, such as building construction, landscaping, farming, archeological excavation, cotton mill work, military training, and recreational pursuits (86; 92; 106). Natural events that generate dust clouds, such as earthquakes and windstorms, also increase the risk of infection and have resulted in large outbreaks (88).

Cases reported from endemic states, such as California and Arizona, have risen 10-fold due to multiple factors including increased awareness, surveillance, climate changes, and disruption of soil (22). From 2000 to 2018, the incidence in California has increased nearly 800% (110). In California, analysis of all coccidioidomycosis-associated hospitalizations between 2000 and 2011 found a total of approximately 25,000 hospitalizations, with 13% related to meningitis, and an overall a cost of more than $2 billion dollars (111).

At-risk populations. Certain groups of patients are at a higher risk for developing disseminated disease following a primary pulmonary infection. These are patients with depressed cellular immunity, such as people living with HIV (PLWH) (105) and those on corticosteroids or other immunosuppressive treatment (01; 134). Specifically, immunosuppression in the setting of organ transplantation, biological response modifiers (ie, inhibitors of tumor necrosis factor), and other disease-modifying antirheumatic drugs are associated with increased risk (76; 119; 59). Interestingly, the incidence of severe coccidioidomycosis has declined considerably in people living with HIV with the development of potent antiretroviral treatment, and the severity of infection is inversely related to the control of HIV (04; 69). Patients with hematological malignancies are also at a higher risk for disseminated coccidioidomycosis; the immunological impairment in these patients is due to the disease itself or to its treatment (16). Pregnancy carries an increased risk of dissemination, especially if the disease is acquired or reactivated during third trimester or immediately postpartum (91; 20; 13). Certain racial groups have a greater susceptibility for infection. African Americans are at a higher risk for coccidiomycosis and for disseminated disease (110; 12). Filipino ethnicity also increases the odds of disseminated disease (12). A few studies have suggested that the highest hospitalization rate is among American Indians and Alaska Natives (73), and the highest mortality is among American Indians (54), but the studies have been limited by small numbers.

Diagnostic workup

	• Culture of Coccidioides from CSF establishes the diagnosis, but CSF cultures are hampered by low sensitivity.
	• A presumptive CNS diagnosis is often made based on clinical history, presentation, and detection of anticoccidioidal antibodies in serum or, ideally, detecting antibodies or antigen in CSF.
	• Neuroimaging may reveal hydrocephalus, basilar meningitis, and cerebral infarcts.

The definitive method of establishing the diagnosis of coccidioidomycosis is by isolation of the organism from a clinical specimen. Coccidioides is not a fastidious fungus to culture and is readily grown on most media used in clinical microbiological laboratories. However, culture sensitivity is influenced by site of infection and sample cultured (respiratory samples from sputum or bronchoalveolar lavage are most sensitive), host immune status, and fungal burden (75). It is also a relatively rapidly growing fungus, so it is often detectable within 5 days and sometimes as early as 2 days after the medium is inoculated. It is important to notify the laboratory if infection by Coccidioides is suspected to minimize the risk of inadvertent accidental exposure of laboratory personnel. In the mycelial form, definitive identification by the colony morphology is not possible, and the organism must be identified by other means, such as DNA-specific probes or matrix-assisted laser desorption ionization mass spectrometry (117; 75).

Tissue specimens offer potential for rapid diagnosis because stains of mature spherules with endospores are pathognomonic for infection. Typical spherules are rarely seen in CSF, although they are found in clinical specimens from extra neural tissue and assist in establishing an early definitive diagnosis. A 2021 guideline from the European Confederation of Medical Mycology states that finding spherules in a clinical specimen “is considered proven disease, even in the absence of positive culture results” (122).

The diagnostic approach typically includes imaging, CSF examination, serological testing, urine testing, and histological study of involved extra neural tissues.

Radiographic studies

Neuroimaging. Early in the disease course, coccidioidal meningitis shows enhancement in the basal cisterns, sylvian fissures, and pericallosal regions. In later stages of the disease, ventriculitis, hydrocephalus (communicating or noncommunicating), and deep infarcts may be observed (137; 38).

In a series of 62 cases, the most common abnormal brain imaging was hydrocephalus (52%), basilar meningitis (47%), and cerebral infarction (39%). Development of hydrocephalus or hydrocephalus in combination with cerebral infarction is suggestive of higher morbidity and mortality rates (06). In another series of 23 cases, when MR angiography was performed, 30% had irregularities in intracranial vessels (65). Intracranial vasospasm rarely occurs secondary to vasculitis and can be evaluated by transcranial doppler ultrasound or conventional angiography (53).

The most common abnormal spinal imaging noted in a series of 41 cases was leptomeningeal enhancement, adhesive arachnoiditis (most frequently in lumbar regions), and osteomyelitis or discitis, which may resemble tuberculous or pyogenic infection. Less common manifestations were cord edema and syrinx, both of which were seen equally in the cervical and thoracic regions. Skip lesions were common, indicating the need for imaging of the entire neuroaxis (26).

When intracranial abnormalities were present, 86% had concomitant spinal abnormalities (65).

Chest x-ray and other imaging. Nearly 90% of the patients with coccidioidal meningitis have abnormal chest radiographs. The lesions include unilateral or bilateral infiltrates, miliary patterns, thin-walled cavities, old granulomatous lesions, pleural effusions, and hilar adenopathy. Bone scans and bone surveys may show foci of osteomyelitis.

CSF examination

The opening pressure is elevated in most patients. CSF analysis often has a lymphocytic predominance (but can be neutrophilic early in the course) with pleocytosis typically ranging from double digits to hundreds, but it can be into the thousands (127). A mononuclear response is characteristically found, and about 70% have eosinophils in the spinal fluid. This is a unique finding among fungal meningitides. In some patients, CSF eosinophils exceed 10/mm3 of CSF (17; 96). However, a study of 133 patients with coccidioidal meningitis demonstrated lymphocytic pleocytosis in 91% and CSF eosinophilia in only 24% (107). Nearly 75% of the patients also have a low glucose, often below 40, and 88% have an elevated protein concentration.

Serological testing

Antibody detection in serum. Diagnosis can be challenging in the absence of a positive culture. Multiple serologic tests to detect IgM and IgG antibodies to coccidioidomycosis exist; the two most utilized are enzyme immunoassay (EIA) and immunodiffusion (ID). Immunodiffusion testing is more specific than enzyme immunoassay, and in some cases recommended as a serologic confirmatory study after a positive enzyme immunoassay. In the proper clinical context, a positive result on either enzyme immunoassay or immunodiffusion supports a diagnosis of coccidioidomycosis (75; 46). In primary infection, IgM antibodies (historically and in some laboratories still reported as tube precipitin or precipitins with an immunodiffusion assay) occur in about 75% of patients. These gradually disappear and are not seen in chronic infection. Conversely, IgG antibodies (historically and in some laboratories reported as complement fixation with an immunodiffusion assay, not be confused with the below different laboratory technique of complement fixation [CF]) are usually found in chronic infection and persist in relation to the extent of disease (23; 75).

Additional serologic tests include a lateral flow assay (LFA) and complement fixation (CF). The lateral flow assay detects IgM and IgG antibodies to coccidioidomycosis and has the advantage of rapid turnaround with results available in as little as one hour. However, the lateral flow assay is not readily available in all settings and has a lower sensitivity at 31% compared to enzyme immunoassay (33; 75). Complement fixation, providing a quantitative assessment of coccidioidal IgG antibodies, along with immunodiffusion, remains one of the benchmark techniques for diagnosis (75). False positive complement fixation tests are rare, but complement fixation is less sensitive than immunodiffusion. If the infection resolves, complement fixation antibodies usually disappear. However, continued infection results in persistently elevated titers. Furthermore, graded changes in the antibody titer reflect the course of the disease.

With the array of serologic testing available for coccidioidomycosis, having a suggested diagnostic algorithm is useful. The Centers for Disease Control and Prevention (CDC) recommend an enzyme immunoassay with confirmatory immunodiffusion or CF for diagnosis. More information can be accessed at the following site: https://www.cdc.gov/valley-fever/hcp/testing-algorithm.

Importantly for all serologic testing in immunocompromised patients, the serologic response may be delayed or absent, and if initial results are negative but suspicion is high, repeat testing is recommended.

Antibody and antigen detection in CSF. Multimodal CSF testing is recommended with immunodiffusion and/or CF antibody testing as well as CSF coccidioidal antigen. In a retrospective cohort of 36 individuals with coccidioidal meningitis, of those with positive results, 7% had positive CSF cultures, 67% had CSF antibodies by immunodiffusion, 70% had CSF antibodies by complement fixation, 8% had reactive IgM enzyme immune assay, and 85% had reactive IgG enzyme immune assay. In this same cohort, CSF antigen testing demonstrated 93% sensitivity and 100% specificity (60). A different retrospective cohort of 133 participants with coccidioidal meningitis found that 16% had positive CSF cultures, 86% had CSF antibodies by complement fixation, and 52% had coccidioidal DNA detected in CSF by PCR (107). By combining CSF testing results, sensitivity and specificity can be further optimized; if CSF antibodies by immunodiffusion and by complement fixation and CSF antigen were combined, sensitivity was 98% and specificity was 99%. Similar findings were demonstrated in a study evaluating CSF diagnostics, which found optimal tests in CSF by combining antibody detection by complement fixation with antibody detection by immunodiffusion or by combining information from IgG and IgM enzyme immune assays, as IgM assays alone were less sensitive (114).

Antigen and DNA detection. Antigen testing is commonly done in the serum but also in CSF (as discussed above) and urine. The ability to detect circulating antigen and the presence of specific DNA sequences of coccidioidomycosis are possible additional tools to aid in diagnosis. Antigenuria in those with severe coccidioidomycosis can be proven by using a specific Coccidioides antigen enzyme immunoassay with antibodies to galactomannan, which is superior to using a Histoplasma enzyme immunoassay where cross-reactivity is present. Of those with coccidioidomycoses, 71% had a positive urine Coccidioides immunoassay compared to 58% positivity with the urine Histoplasma immunoassay (37). When aiming to detect the early phase of infection, urine antigen detection by enzyme immunoassay is twice as sensitive as serum antibody detection (131). Additionally, antigen testing in the CSF can be positive even in those who are immunosuppressed and can be followed over time to detect disease burden (09). As previously referenced, CSF antigen testing can be combined with CSF antibody detection by immunodiffusion and complement fixation to improve testing of diagnostic yield (60).

Skin testing

Coccidioidin skin testing is more useful to assess for prior exposure than as an applicable diagnostic tool. The skin test is usually positive in only 25% patients with coccidioidal meningitis (17).

Other laboratory studies

Of those with meningitis, one third have peripheral blood leukocytosis, and about one half have a peripheral eosinophilia (17). A derivative of fungal cell walls, (1,3)-beta-D-glucan, can be tested in both the serum and CSF as a screening test to differentiate between fungal and other etiologies of meningitis, as it has been shown to be detectable in infection with Coccidioides among other invasive mycoses (120; 116). Additional tests to consider include polymerase chain reaction (PCR) and next-generation sequencing (NGS). PCR may be applied to serum, CSF, other fluids, or tissue, but is limited in availability to in-house laboratories, and only one is Federal Drug Administration approved (and only for bronchial alveolar samples) (75; 46). Next-generation sequencing looks at genomic DNA fragments from a clinical sample and in some cases may identify infectious etiologies such as coccidioides (75).

Management

	• Azoles are the fungistatic therapy of choice.
	• The standard treatment for Coccidioides meningitis is fluconazole, which offers excellent CNS penetration; however, it should be continued for life.

The Infectious Disease Society of America published practice guidelines for treatment of coccidioidomycosis (44). These are also available online at http://www.IDSociety.org.

Drug treatment

Given similar disease morbidity and mortality with azoles compared to intrathecal amphotericin B, azoles are often first line therapy due to decreased side effects and burden of treatment (58). Azole antifungal drugs for treatment of Coccidioides meningitis include the following (44):

• Fluconazole: 400 to 1200 mg/day orally or intravenous
• Itraconazole: 200 mg orally every 8 or 12 hours
• Voriconazole: 4 mg/kg orally every 12 hours
• Posaconazole: 400 mg every 12 hours

For meningitis, therapy with oral fluconazole is currently preferred (44). The dosage used in reported clinical trials was 400 mg/day (43) and may be escalated if clinical or CSF parameters fail to improve. Some clinicians start treatment with 800 to 1200 mg/day. About 80% of patients improve with treatment. The clinical symptoms respond earliest, followed by improvement in CSF pleocytosis. CSF antibody titers are the slowest to remit and, in general, diminish over 4 months after initiation of treatment. Itraconazole in doses of 400 to 600 mg/day is reported to be equally effective as fluconazole (124); measurement of serum concentrations after 2 weeks is advised to determine that absorption is satisfactory. Patients who respond to azole therapy should continue this therapy indefinitely because the relapse rates on discontinuation of treatment are as high as 75% (30).

In those that relapse, if initially treated with fluconazole 400 mg/day, options include increasing the dose to 800 to 1200 mg/day (43). Other options include transitioning to another azole (commonly itraconazole, voriconazole, or posaconazole) or considering intrathecal amphotericin B (05; 61; 101). Experience suggests that with fluconazole, prolonged remissions are not always achieved with continued use of this agent (113). There are reports of effective use of high dose voriconazole in fluconazole-resistant coccidioidal meningitis (25; 95). Favorable outcomes were seen within the first 2 months of initiation of treatment with voriconazole in patients with relapse (42).

Patients treated with azoles need close monitoring for drug levels, with ranges varying by institution, as well as attention to hypokalemia, hypomagnesemia, hypocalcemia, elevated transaminases, adrenal insufficiency, and QT prolongation. Prior to initiation of itraconazole, patients should have an echocardiogram and measurement of brain natriuretic peptide due to a black box warning for patients with heart failure. Additionally, itraconazole absorption is enhanced by food and acidity, so it should be given with fatty food and an acidic beverage. Drug interaction with itraconazole is a limiting factor, especially in transplant patients receiving calcineurin inhibitors (63). Super-bioavailability itraconazole may offer an alternative to conventional itraconazole with the advantage of being less subject to food and acid effects. One randomized trial comparing super-bioavailability itraconazole to conventional itraconazole in 88 participants with endemic mycoses (13 with coccidioidomycosis) found comparable bioavailability at one-third lower doses and fewer adverse effects (112). Voriconazole can cause a severe photo dermatitis and reversible visual changes and patients should be counseled to wear protective eyewear and clothing against ultraviolet radiation. Voriconazole has drug interactions with antiretroviral agents, especially ritonavir and efavirenz (71).

In the past, intrathecal amphotericin B was administered in addition to an azole in the belief that responses are more prompt with this approach. However, intrathecal treatment is now reserved for treatment failure and refractory cases, arachnoiditis, or development of syrinx. The optimal dose and duration of intrathecal amphotericin is not established. Intrathecal therapy can be administered through direct cisternal puncture, lumbar puncture, lumbar reservoir, and ventricular Ommaya instillation. Experience by one group in an endemic region suggests a regimen of initiation at 0.1 mg three times per week and gradual increase of the dose by 0.1 mg per week as tolerated. The dose is titrated to tolerability ranging from 0.2 mg up to 0.9 mg/day per dose. CSF continues to be monitored and with improvement, frequency of dosing is decreased over time. Concurrent administration of intrathecal steroids reduces risk of arachnoiditis (52). Complications of intrathecal therapy include pain, headaches, paresthesia, and nerve palsies that are caused by the direct neurotoxic effects of amphotericin B or result from amphotericin-induced arachnoiditis (115). In a patient with refractory coccidioidal meningitis, continuous infusion of amphotericin B through a programmable implanted pump resulted in response to treatment, suggesting a new route of drug delivery for chronic meningitis (14).

The role of glucocorticoids for management remains unclear but anecdotal evidence suggests administration primarily in those with vasculitic infarction with dosing of dexamethasone 20 mg daily divided intravenously for 7 days followed by a taper of 4 mg every other day (44; 121).

At-risk populations

Transplant. There are case reports and case series regarding treatment in the setting of solid organ (renal, liver, heart, lung, small bowel) and autologous or allogenic hematopoietic stem cell transplants. Two general strategies have emerged, with the first being amphotericin B (or lipid associated amphotericin B) with concurrent or sequential use of an azole. Concurrent use was reserved for those with severe infections or when toxicities limited consistent dosing of amphotericin B. Voriconazole was most often used with stem cell transplant recipients. The second strategy is treatment with azoles alone, although, as discussed previously, azoles can interfere with clearance of calcineurin inhibitors and sirolimus, requiring dose adjustments of the immunosuppressant (63; 44). Current recommendations from the American Society of Transplantation recommend prior to transplant, candidates should be screened for risk of exposure to Coccidioides (ie, traveled to or living in endemic area). For solid organ transplant recipients in endemic areas, regardless of pretransplant serostatus, oral azole prophylaxis should be given for a minimum of 6 to 12 months. If patients have a history or evidence of prior coccidioidomycosis, lifelong secondary azole prophylaxis (200 to 400 mg per day) is recommended given the high risk of relapse (77).

Biological response modifiers or disease modifying antirheumatic drugs. In a series of 44 patients on these agents, nine had disseminated disease, but none to the central nervous system, making it difficult to extrapolate findings. However, consideration should be given to discontinuation of biological response modifiers or disease-modifying rheumatic drugs in those with disseminated coccidioidomycosis, with caution in restarting these therapies in those with asymptomatic or pulmonary coccidioidomycosis (119).

Pregnancy. Due to teratogenicity, azoles should be avoided in the first trimester of pregnancy and intrathecal amphotericin B therapy should be used with transition to either fluconazole or itraconazole in second and third trimesters (13; 44).

HIV. In patients with coccidioidal infection and HIV, use of combination antiretroviral and antifungal therapy is recommended regardless of CD4 T lymphocyte count (69). Initiation of antiretroviral therapy should not be delayed due to concern for immune reconstitution inflammatory syndrome, as this disorder is rare with coccidioidal infection (123). All azole antifungals have the potential for interaction with antiretroviral therapy, and the choice of azole is dependent on the antiretroviral regimen (70).

Interferon gamma deficiency. Refractory coccidioidal meningitis in one patient with interferon gamma deficiency was successfully treated with a combination of voriconazole and adjuvant interferon gamma 1b, with improvement seen after 8 months of combination treatment, but further investigation is needed for the use of interferon gamma 1b as an adjunctive therapy in this population (29).

Surgical intervention

Symptomatic hydrocephalus almost always requires shunting and there is limited literature on management of acute hydrocephalus. The initial approach can be similar to that described in patients with cryptococcal meningitis with acute management involving serial lumbar punctures and removal of CSF to reduce pressure by 50% of the opening pressure or to 200 mm of H2O, whichever is greater. If intracranial pressure fails to improve despite at least four lumbar punctures then consideration should be made for placement of an external ventricular drain, lumbo-peritoneal shunt, or ventriculo-peritoneal shunt. In the setting of isolated fourth ventriculomegaly, options include endoscopic aqueductoplasty, stenting of the cerebral aqueduct, or placement of a dedicated fourth ventricular catheter as part of a ventriculoperitoneal shunt system (66). If asymptomatic hydrocephalus is present, serial imaging every 3 to 6 months should be obtained until stability is seen (44).

Prompt treatment of elevated intracranial pressure with surgical intervention is thought to outweigh theoretical potential of infectious nidus at the end of the catheter tip. There is a risk of shunt failure, most commonly due to mechanical clogging from proteinaceous debris. If there is concern for shunt infection, lumbar puncture and shunt tap should be performed for culture. In the context of shunt failure, if no new organism is cultured, the shunt should be removed and replaced. If bacterial shunt infection is present, the shunt should be removed with temporary external ventricular drain placement until CSF is sterilized and then new shunt can be placed (50).

A rare case of vasospasm secondary to infectious vasculitis that was successfully treated with percutaneous transluminal angioplasty is reported (53).

In spinal coccidioidomycosis, surgical treatment is indicated in patients with spinal instability, neurologic deficits, abscess formation, osteolysis, poor response to fungal therapy, or continued intractable pain with an attributable focus of infection. Surgical intervention often involves debridement of infected tissue and instrumented fusion. Titanium hardware has been safely used, which is resistant to biofilm formation (97).

Monitoring treatment response

Treatment should be lifelong for coccidioidal meningitis. The optimal treatment duration for other forms of coccidioidal infection remains unclear, especially in disseminated disease, but there is ongoing interest in following biomarkers to determine treatment response. Biomarkers of interest include Coccidioides antibodies, (1,3)-beta-D-glucan, and Coccidioides DNA by specific qPCR in serum, but there are no clear guidelines regarding this approach (133). The European Confederation of Medical Mycology’s 2021 global guideline recommends repeat serological complement fixation quantitative testing every 12 weeks during treatment to follow treatment response (122).

Outcomes

In a retrospective cohort of individuals with coccidioidomycosis within the Veterans Affairs Armed Forces who did not receive antifungal treatment, mortality at last known follow-up was 0.65% in nondisseminated disease, 25% in disseminated disease, and 88% in central nervous system dissemination (12).

Labadie and Hamilton reviewed the survival of 505 patients with coccidioidal meningitis receiving amphotericin B (64). They reported seven separate studies published between 1964 and 1986. The overall survival rate was 56.6%, ranging from 51% to 100%, depending on drug dosing, patient factors, and length of observation. In 1993, Galgiani and colleagues reported an 80% survival rate beyond 2 years for those receiving fluconazole with coccidioidal meningitis (43). A similar survival rate was also reported for patients treated with itraconazole (124).

According to the analysis by Bouza and colleagues of 31 patients and another 114 patients from the literature, 59 patients survived and 37 returned to full-time work after treatment for coccidioidal meningitis (17). The morbidity in some patients involved symptoms from the earlier meningitis and subsequent arachnoiditis. A cohort of 30 cases from 1993 to 2008 was evaluated and compared to the 1980 cohort described by Bouza and colleagues (71). Mortality was almost identical at approximately 40%, and morbidity was similar, with about 40% able to carry out activities of daily living. Notable differences were fewer patients being able to return to some type of employment, though it remained unclear whether these findings were influenced by higher rates of HIV in the newer cohort (71).

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Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Author

Arielle P Davis MD

Dr. Davis of the University of Washington has no relevant financial relationships to disclose.
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Editor

Christina M Marra MD

Dr. Marra of the University of Washington School of Medicine has no relevant financial relationships to disclose.
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Former Authors

John B Selhorst MD
Chitharanjan V Rao MD MRCP
Aarti U Jerath BA
Chandan Reddy MD
Nivedita U Jerath MD
Sandeep Khot MD
Amita Singh MD

Patient Profile

Age range of presentation: 0 month to 65+ years
Sex preponderance: male>female, 4:1
Heredity: none
Population groups selectively affected: African Americans

American Indians and Alaska Natives

Hispanics

Asians, especially Filipinos

Caucasians
Occupation groups selectively affected: building construction workers

landscapers

farmers

archeologists

cotton mill workers

military personnel

agricultural workers

ICD & OMIM codes

ICD-10: Coccidioidomycosis meningitis: B38.4

Disseminated coccidioidomycosis: B38.7
ICD-11: Pulmonary coccidioidomycosis: 1F25.0

Extrathoracic coccidioidomycosis: 1F25.1

Coccidioidomycosis, unspecified: 1F25.Z

Disseminated coccidioidomycosis: 1F25.10

Coccidioides meningitis: 1F25.12

Other specified erythema multiforme: EB12.Y

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Coccidioidomycosis: neurologic manifestations

Associated Disorders

arachnoiditis
arthroconidia
cavitary lung lesions
coccidioidin
coccidioidomycosis
- cranial and vertebral osteomyelitis with associated neurologic complications
- CSF eosinophilia
- encephalitis
- hydrocephalus
- infarction
- leptomeningitis
- meningitis
- meningoencephalitis
- parenchymal granulomas and abscesses with or without meningitis
- spondylitis
- strokes
- vasculitis

Differential Diagnosis

acute bacterial and viral meningitis
acute bacterial and viral encephalitis
neurotuberculosis
brucelosis
cryptococcosis
- aspergillosis
- histoplasmosis
- CNS candidiasis
- bacterial endocarditis
- neuroborreliosis
- Behçet disease
- parameningeal suppurative foci
- carcinomatous meningitis

Coccidioidomycosis: neurologic manifestations

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Confusing conditions

Diagnostic workup

Radiographic studies

CSF examination

Serological testing

Skin testing

Other laboratory studies

Management

Drug treatment

At-risk populations

Surgical intervention

Monitoring treatment response

Outcomes

Special considerations

Pregnancy

References

Contributors

Author

Editor

Former Authors

Patient Profile

ICD & OMIM codes

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