Coccidioides Immitis Meningoencephalitis
This patient developed a subacute progression of headache, left third nerve palsy (with anisocoria but equal pupillary reactivity), ataxia, irritability and confusion, nuchal rigidity and fever. This clinical presentation suggested a basilar meningoencephalitis as the most likely process unifying the patient's complaints. Imaging findings suggested leptomeningeal disease with a predominance at the base of the brain, and an abnormal area of enhancement in the posterior right frontal cortex, together with infarction in the basal ganglia and dorsal midbrain. CSF examination showed pleocytosis, protein elevation, and hypoglycorrhachia, most consistent with acute infection.
Subarachnoid hemorrhage, endocarditis or septicemia, diffuse metabolic disturbances, and CNS involvement by malignancy had also been considered as possible explanations of the patient's condition. Imaging and CSF examination did not support a diagnosis of subarachnoid hemorrhage, and no mass effect was seen. The clinical examination, blood cultures and an echocardiographic study did not suggest endocarditis. Imaging findings and a negative cytologic screen of CSF were not felt to support a high likelihood of malignancy. Several causes of inflammation, including lupus erythematosus and sarcoidosis, were felt to be unlikely due to lack of clinical involvement suggesting these disorders, even though laboratory screens showed nonspecific abnormalities.
Given the high clinical and laboratory suspicion for an acute infection in a patient with underlying immunosuppression (autoimmune hepatitis, immunosuppressive treatment), an array of serologic studies, smears and cultures was obtained. A study for C. immitis antibodies was positive in both serum and CSF, with screens for fungi, mycobacteria, and other pathogens reported as negative. Based on these data, the clinical team initiated treatment with intravenous amphotericin B. The hypothesis of C. immitis infection was confirmed by culture of the organism from CSF. Following the diagnosis, we obtained the additional history that the patient had been exposed to flowers brought from Arizona, a location in which C. immitis has been documented as an endemic pathogen, some time during the month before her onset of symptoms.
Coccidioidomycosis is a systemic fungal infection due to Coccidioides immitis, endemic to some deserts of the Western Hemisphere. (1) C. immitis is a dimorphic fungus classified as an ascomycete by ribosomal gene homology. In its vegetative state, mycelia with true septations mature to produce arthroconidia. After infection, an arthroconidium enlarges to form a spherule, undergoing internal septation to produce scores of endospores. Ruptured spherules release endospores that may then produce more spherules in infected tissue or revert to mycelia if removed from the body.(1)
C. immitis can be recovered from the soil of the low deserts of Arizona; the Central Valley of California; and parts of other states, including New Mexico, West Texas and the Rio Grande Valley; and parts of Central and South America. Endemic regions tend to follow the climatologic Sonoran life zone, which is characterized by modest rainfall, mild winters, and low humidity. Mycelia bloom beneath the surface during periods of rain, and arthroconidia develop as the earth dries. Rates of infection are highest during dry months and are accentuated when soil is disturbed by windstorms or construction equipment. Exposure to contaminated bales of cotton or other fomites can result in infection beyond the endemic regions, but this is rare. Person-to-person transmission of pulmonary infection has not been reported, and isolation precautions are unnecessary.(1, 3)
In general, the annual risk of infection within the most strongly endemic areas is 3%, and results in approximately 100,000 new infections per year. With unusually intense exposure, such as at archeology sites or during military maneuvers within endemic regions, infections can develop in the majority of persons exposed, even if for only a few days. More than 60% of new infections are reported in Arizona, presumably because of the rapid growth of populations in the Phoenix and Tucson areas.
Inhaling an arthroconidium to the level of the terminal bronchiole initiates virtually all coccidioidal infections. Fungal proliferation engenders both granulomatous inflammation, which is associated with intact spherules, and acute inflammation including eosinophils, which is associated with spherule rupture. Focal pneumonia may develop, often associated with ipsilateral hilar adenopathy; less frequently, infection enlarges peritracheal, supraclavicular, and cervical nodes. Lesions occurring elsewhere are felt to result from hematogenous dissemination and most become apparent within 2 years of the initial infection. Although progressive, clinically evident dissemination results from fewer than 1% of infections, as many as 8% of persons with self-limited infection manifest asymptomatic chorioretinal scars, suggesting that subclinical hematogenous spread may be frequent. Within weeks after infection, durable T-cell immunity normally arrests fungal proliferation, allowing inflammation to resolve and preventing reinfection in the future. However, host control of the infection may occur without actually sterilizing the infective lesions, and reactivation of dormant infection or second infections is possible in patients whose cell-mediated immunity becomes deficient.(4)
Establishing a diagnosis of CNS fungal infection is a challenge because the clinical presentation is nonspecific, and isolating the fungus from the CSF or the brain is difficult. Helpful clues to the diagnosis often include geographic location, risk factors, evidence of infection of other systemic organs, and fungal serologic tests. Typical CSF findings in fungal meningitides are: variable opening pressure, moderately elevated (20-500) WBC counts, elevated protein, low CSF glucose (often < 40 mg/dL), and negative gram stains. The sensitivity of CSF cultures to detect fungi is modest (positive in about 75% of cases of Cryptococcus neoformans meningitis, but only about 53% of cases of Histoplasma capsulatum meningitis, 46% of cases of Coccidioides immitis meningitis, 44% of cases of Candida sp. meningitis, and less often in cases caused by Blastomyces dermatitidis or other fungi.[ ] Sensitivity and specificity of CSF culture may increase with repeated examinations of larger volumes of CSF.
Although definitive diagnosis of coccidioidal meningitis is made by identification of C. immitis by culture or stain of tissue or fluid, diagnosis is often made by detection of specific IgG antibody in the CSF using complement fixation or ELISA.[12] A limitation of this approach is that the IgG antibody may be absent early in symptomatic infection. Interpretation of serum tests may be difficult, due to the effects of unknown stage of infection, blunting of antibody response by immunosuppression, and cross-reaction on the antibody assay. High titers of specific antibody in serum (>= 1:32 dilutions) are felt to increase the likelihood of an active systemic infection.(13) For most currently available fungal antibody tests, such as the CF, ELISA, and immunodiffusion assays, a positive CSF test highly suggests an active CNS infection.(15)
The most common presentation of a patient with CNS fungal infection is that of subacute meningitis. Occasional patients present with a chronic meningitis (longer than 4 weeks duration), and less commonly, with an acute meningitis. Signs and symptoms gradually develop over 1 to 2 weeks. Among patients with disseminated disease, almost all develop a subacute meningitis, and rarely a coccidioidal brain abscess may develop. The meningitis is typically more intense than is seen in cryptococcal meningitis. Prominent basilar meningitis frequently leads to development of hydrocephalus, and meningeal vasculitis may cause occlusions of arteries, leading to cerebral infarctions, as were seen in this patient's case.(6, 7, 8) Patients with CNS granulomas may clinically present as a combination of brain masses, meningitis and strokes.
Fluconazole is effective therapy for coccidioidal meningitis and has greatly reduced the number of patients treated with intrathecal amphotericin B. Unfortunately, cessation of azole therapy for coccidioidal meningitis is often followed by recurrence of symptoms. Therefore, many patients may need protracted or even life-long therapy to maintain control of disease. Amphotericin B remains a rational choice in cases in which treatment with azole antifungals has failed, or in patients with rapid disease progression. Surgical removal of necrotic tissue is sometimes necessary to control the damage from specific lesions.(9)
Untreated CNS fungal infections are almost always fatal. For immunocompetent patients receiving antifungal treatment, rates of cure or chronic suppression of disease are about 50% for coccidioidal meningitis.(10) Neurological complications develop in approximately 50% to 75% of patients with coccidioidal or histoplasmal meningitis.(11) One of the most common neurological complications of fungal meningitis is obstructive hydrocephalus requiring ventriculoperitoneal shunting. This complication develops in coccidioidal or histoplasma meningitis in 25% to 50% of the affected population. Early detection, aggressive therapy and surveillance for recurrence, and if possible, management of the immunosuppressed state are therefore critical to treatment of patients with C. immitis infection.
We gratefully acknowledge the contribution of Dr. George Ringholz, of the Neurology Service at The Methodist Hospital, to this case presentation.
-- Dennis R. Mosier, M.D., Ph.D.
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