CASE 1 A previously well 16-year-old African-American young man presented to the Emergency Department (ED) at Children's Hospital and Research Center at Oakland (CHRCO) with persistent vomiting, severe headaches, and decreased energy of 5 weeks duration. Five weeks earlier, the patient had presented to his pediatrician with headache and vomiting. He was treated with oral amoxicillin for presumed streptococcal pharyngitis, but the group A Streptococcus antigen test was negative. Three weeks later, he presented to a local ED with worsening nausea, vomiting, dizziness, poor oral intake, worsening headaches, neck stiffness and fever. Physical examination was significant for a strange affect, belligerent behavior and neck stiffness, but no other abnormalities were found. The evaluation included an examination of cerebrospinal fluid (CSF) which revealed a red blood cell count (RBC) of 3/mm3; white blood cell count (WBC) of 380/mm3 with 25% neutrophils, 66% lymphocytes and 9% monocytes; protein 148 mg/dL; and glucose 15 mg/dL. He was treated with ceftriaxone for possible bacterial meningitis. Further evaluation revealed a normal chest radiograph, no induration in response to a purified protein derivative (PPD) tuberculin skin test, a normal cranial computed tomography (CT) scan and a normal electroencephalogram. The CSF culture had no growth of bacteria and no organisms identified on Gram stain. After 4 days of treatment with ceftriaxone, he was discharged home with a revised diagnosis of presumed viral meningitis. During the next 2 weeks, he continued to have vomiting, headache, decreased energy and intermittent fevers. Because he appeared worse to his parents, he was brought to the ED at CHRCO for reevaluation. Additional history revealed that the patient had traveled to Corpus Christi, TX, 6 months before this evaluation. He was an avid insect collector and had collected some ants with local soil into a jar and brought them home from this trip. One month after his trip to Texas, he had traveled to Porterville, CA, and swam in the Tule River near there. At home, he had a pet tarantula and a puppy. He admitted to occasional marijuana and alcohol use. No other family members had been recently ill. Family history was significant only for his father's heart disease. On physical examination, he was lethargic with a flat affect. He was sleepy but arousable and answered questions appropriately. Temperature was 38°C, and other vital signs were normal. He had a stiff neck and dry mucous membranes, but otherwise a normal examination, including normal cranial nerves, brisk but symmetric lower extremity reflexes and normal strength in all extremities. Laboratory findings included a WBC of 7,700/mm3, hemoglobin 13.1 g/dL, platelet count 365,000/mm3 and a normal metabolic panel except for sodium 129 mEq/L and chloride 94 mEq/L. The erythrocyte sedimentation rate was 22 mm/h. A cranial CT scan revealed a focal area of decreased attenuation in the region of the left posterior thalamus. CSF contained RBC 1/mm3; WBC 737/mm3 with 33% neutrophils, 51% lymphocytes, 15% monocytes and 1% macrophages; protein 176 mg/dL; and glucose 9 mg/dL. He was initially treated with ceftriaxone and vancomycin for possible bacterial meningitis. This was then changed to isoniazid, rifampin, pyrazinamide and ethambutol for possible tuberculous meningitis. A wet mount examination of the CSF revealed cells with variable appearance that changed shape over time and were thought to be consistent with amebic trophozoites. Accordingly a diagnosis of amebic meningitis was considered, and antituberculosis medications were stopped. On the basis of in vitro studies of various antimicrobial agents that have activity against Balamuthia,1,2Naegleria and Acanthamoeba,3,4 and the rapidly fatal nature of amebic meningitis, the patient was treated with liposomal amphotericin B, fluconazole, trimethoprim-sulfamethoxazole, azithromycin, rifampin, flucytosine, pentamidine and chlorpromazine. The CSF culture was negative for bacteria, viruses and acid-fast bacilli, and a cryptococcal antigen test was negative in the CSF. Serial examinations of the CSF demonstrated encouraging signs of improvement with decreasing WBCs, decreasing protein and increasing glucose. Attempts to identify the ameboid-like cells as Balamuthia, Naegleria or Acanthamoeba were unsuccessful. The CSF failed to grow amebae in specialized culture media, performed at the Viral and Rickettsial Disease Laboratory, California Department of Health Services, Richmond, CA. Serologic tests on the patient's blood for these amebae were nonreactive. Flucytosine, amphotericin, pentamidine and chlorpromazine were stopped. He was discharged home to continue trimethoprim-sulfamethoxazole, fluconazole, azithromycin and rifampin empirically. At discharge, his CSF contained RBC 150/mm3; WBC 36/mm3 with 34% neutrophils, 54% lymphocytes, 11% monocytes and 1% eosinophils; protein 85 mg/dL; and glucose 39 mg/dL. About 6 weeks after discharge, CSF analysis revealed RBC 2/mm3; WBC 300/mm3 with 29% neutrophils, 44% lymphocytes and 27% monocytes; protein 104 mg/dL; and glucose 30 mg/dL. The patient admitted to being nonadherent to his medications. He was reevaluated because of the worsening CSF indices and the inability to prove amebae as the etiology of his meningitis. Then a diagnostic test was performed. CASE 2 A 19-month-old Filipino-Latino male toddler presented to the ED at CHRCO with difficulty walking for 6 days. He was lethargic at home with decreased energy and activity and was unsteady on his feet, falling with attempts to walk. His past medical history was significant for recurrent respiratory illnesses and asthma exacerbations since ∼1 year of age. He had received several courses of antibiotics for pneumonia and otitis media, and oral steroids for asthma exacerbations during the last year. In addition, the family noticed that during the previous 6 months, he appeared more tired and required more frequent naps. He was emotionally more clingy toward his parents and seemed to be less active than other children his age. His parents were concerned about his possible slow speech development and poor weight gain. He also had recurrent low grade fevers and occasional night sweats. He had exposure to a dog at home, and his only recent travel was to Lake Tahoe, CA. His father had a recent upper respiratory infection but was currently healthy, and his mother reported a recent negative PPD tuberculin skin test and was also currently healthy. Physical examination revealed a temperature of 37.8°C, pulse of 129 beats/min, blood pressure of 98/47 mm Hg, respiratory rate of 28 breaths/min, oxygen saturation of 100% in room air and weight of 9 kg. The patient appeared alert but irritable. He refused to stand or walk during the examination. Otherwise the physical and neurologic examinations were unremarkable. Initial laboratory data included WBC 5,900/mm3, hemoglobin 10.5 g/dL, hematocrit 32% and platelet count 256,000/mm3. Serum sodium was 133 mEq/L, potassium 4.8 mEq/L, chloride 97 mEq/L, bicarbonate 26 mEq/L, blood urea nitrogen 7 mg/dL, creatinine 0.5 mg/dL and glucose 137 mg/dL. A cranial CT scan without contrast showed enlarged ventricles without midline shift or focal lesions or hemorrhage. He underwent emergent placement of a ventriculoperitoneal (VP) shunt to alleviate hydrocephalus. Analysis of CSF from the ventricles obtained during VP shunt placement revealed RBC 340/mm3; WBC 117/mm3 with 4% neutrophils, 65% lymphocytes, 19% monocytes, 4% eosinophils and 8% histiocytes; protein 319 mg/dL; and glucose 25 mg/dL. He received prophylactic cefazolin for the VP shunt surgery. After surgery, a magnetic resonance imaging study of his head revealed leptomeningeal enhancement surrounding the brainstem into the cervical cord as well as moderate communicating hydrocephalus and mild periventricular edema. He became less lethargic, more talkative and more active over the next 3 days. Ventricular fluid taken from the VP shunt 3 days after its placement revealed RBC 13/mm3; WBC 261/mm3 with 21% neutrophils, 26% lymphocytes, 45% monocytes and 8% eosinophils; protein 366 mg/dL; and glucose 27 mg/dL. A wet mount examination of the CSF showed motile cells with ameboid processes. A PPD tuberculin skin test on the patient and the father were nonreactive. The patient's chest radiograph showed mild bronchial thickening without focal infiltrate, effusion, adenopathy or evidence of nodular lung disease. The chest radiographs of both parents were normal. Further workup revealed the diagnosis. For denouement, see p. 1074. Denouement Continued from p. 1068 The cerebrospinal fluid (CSF) and sera from both cases were reactive for the presence of antibody against Coccidioides immitis. The tests were performed at the Coccidioidomycosis Serology Laboratory at the University of California Davis, School of Medicine. In the first case, the CSF was positive for coccidioidal antibody by immunodiffusion test detecting IgM and/or IgG antibody and by complement fixation (CF) detecting IgG antibody. The quantitative CF test revealed a titer of 1/4 in the CSF, and the serum showed a quantitative CF titer of 1/8. In the second case, the serum and ventricular fluid were both positive for coccidioidal antibody by immunodiffusion test. Quantitative immunodiffusion testing yielded a titer of coccidioidal CF IgG antibody of 1/64 in the serum and 1/16 in the ventricular fluid. Cultures of CSF in both cases failed to grow C. immitis. These cases illustrate 2 different presentations of coccidioidal meningitis. The first patient had a subacute presentation with headache, fever, lethargy and vomiting for several weeks. The timely diagnosis for this case was confounded by the finding of motile cells with ameboid processes identified as possible amebic trophozoites in the wet mount examination of the CSF. After closer examination, these cells were thought to be active macrophages, which raised concern about the accuracy of the identification of amebae using wet mount examination. Once the diagnosis of amebic meningitis was excluded, the diagnostic tests for coccidioidal meningitis were requested. Although the patient lived in Oakland, CA, which is not an endemic area for C. immitis, he had traveled to Texas and through the Central Valley of California. His hobby of insect collection may have predisposed him to soil exposure, or he may have breathed in dusty air while traveling through Porterville. The second patient presented with signs of hydrocephalus, a well-known complication of coccidioidal meningitis. His diagnosis was suspected promptly on review of CSF findings and because he resided in Tracy, CA, an endemic area for C. immitis. Although this patient's CSF also had evidence of motile cells with ameboid processes on wet mount examination, the experience gained from the first case led the clinicians to be wary of presuming these were amebae without confirmatory tests. Serologic studies of the CSF and serum and culture of the CSF failed to identify the presence of amebae. Smear for acid-fast bacilli and tuberculosis polymerase chain reaction performed on CSF were negative. Cryptococcal antigen was not detected in serum. C. immitis antibody studies of both CSF and sera confirmed the suspected diagnosis of coccidioidal meningitis. C. immitis is a dimorphic fungus that lives in the soil and is endemic to the southwestern United States (primarily California, Arizona and Texas), Mexico, Central America and South America.5 Inhalation of aerosolized spores from soil disturbances leads primarily to pulmonary infection that manifests as an upper respiratory infection, a lower respiratory infection or asymptomatic infections. Among the symptomatic cases of coccidioidomycosis, fewer than 1% develop subsequent disseminated disease, most commonly involving the skin, musculoskeletal system and meninges, but up to 50% of disseminated cases have meningeal involvement, and this usually occurs within 3 months of the initial presentation.6 Individuals at higher risk for dissemination include males and those with Filipino ancestry, and to a lesser extent African-American race and persons with compromised cell-mediated immunity.7 Clinical presentation can be varied and may manifest as acute, subacute or chronic meningitis similar to tuberculous meningitis.8 Failure to consider C. immitis leads to delayed diagnosis, and Bouza et al6 found a delay in diagnosis of >3 months in >45% of cases reported in the literature. Coccidioidal meningitis usually presents as a chronic granulomatous meningitis, often involving the basilar meninges.7 The most common presenting symptoms include headache, sluggishness, ataxia and vomiting, and children can often lack signs of meningeal irritation.9 Examination of CSF typically reveals moderate pleocytosis with lymphocyte predominance, low glucose and elevated protein concentrations.6 The presence of eosinophilic pleocytosis in the CSF is also common.8 The diagnosis is confirmed by detection of CF antibodies or a positive culture for C. immitis in the CSF. However, CSF cultures are positive in no more than one-half of all patients.8 Without treatment, coccidioidal meningitis is uniformly fatal.8 The current preferred therapy for coccidioidal meningitis is oral fluconazole.10 A dose of 400 mg once a day for adults is appropriate, but doses as high as 800–1000 mg or even 2000 mg have also been used. Itraconazole has also been used with comparable efficacy.10 In children, the dosing range most commonly used is 3–12 mg/kg/d.11 However, the optimal dosage and duration of treatment are unknown. Patients who respond to azole therapy should continue this indefinitely, because relapse rates of up to 75% after stopping therapy have been reported.7 Patients who do not respond to oral azoles are candidates for intrathecal amphotericin B, with or without the addition of an azole. Although not well-defined for coccidioidal meningitis, intrathecal amphotericin B doses range from 0.01 to 1.5 mg, and intervals range from daily to weekly.10 In addition, hydrocephalus nearly always requires decompression by placement of a shunt.10 When the patient in the first case was initially treated for presumed amebic meningitis, his multiple drug therapy included fluconazole and amphotericin B, which may explain his improvement both clinically and in CSF indices. However, when he stopped taking fluconazole, he deteriorated clinically, and his CSF indices worsened. With reintroduction of fluconazole, he again demonstrated improvement in clinical symptoms and CSF indices. He was nonadherent to his medication and was eventually lost to follow-up. In the second case, the patient is being treated with fluconazole at 12mg/kg/d and is being followed at our institution.