A 5-year-old Hispanic girl with a 3-week history of intermittent headaches presented to the emergency department (ED) after a self-limited episode of facial droop and slurred speech. She had an additional episode of facial droop in the ED and was admitted to the pediatric intensive care unit for close monitoring and management.
The child’s medical history was notable for eczema and frequent cold symptoms, prompting adenoidectomy at age 3. She lived in San Diego her entire life with no travel outside of county lines. She did not have any known exposure to tuberculosis, family members with chronic cough, or interaction with individuals who were recently incarcerated. The mother denied any ingestion of unpasteurized dairy products. There was no significant recent contact with animals.
The child was in her usual state of health until 3 weeks before admission, when she started complaining of headaches nearly every morning. The headaches were primarily frontal in nature and were often present upon waking but resolved as the day progressed. She remained afebrile throughout the duration of her illness. On the day of admission, while eating breakfast, the child had a 1-minute episode of right-sided facial droop and slurred speech accompanied by ipsilateral tongue and eye deviation. At the time of the event, she had some difficulty walking but was not syncopal. She returned to baseline after the event with no residual symptoms.
The child was taken to the ED, where she had a temperature of 37.8°C, heart rate of 97 beats per minute, respiratory rate of 19 breaths per minute, blood pressure of 110/78 mm Hg and oxygen saturation of 97%. She initially presented with an unremarkable physical examination; however, while in the ED, she had an additional 1-minute episode of right-sided facial droop and slurred speech that self-resolved.
Urgent magnetic resonance imaging of the brain revealed irregular asymmetric enhancement along the suprasellar cistern and proximal bilateral middle cerebral artery cisterns as well as mild uncompensated communicating hydrocephalus. Magnetic resonance angiography demonstrated marked narrowing of the supraclinoid left internal carotid artery as well as narrowing of the proximal M1 segment of the left middle cerebral artery and A1 segment of the anterior cerebral artery, most consistent with vasculitis (Fig. 1). Chest radiograph was normal.
Laboratory evaluation was remarkable for a white blood cell count of 19 × 103/mm3 (78% neutrophils, 17% lymphocytes and 5% monocytes), hemoglobin of 12.1 gm/dL and platelet count of 286 × 103/mm3. A complete metabolic panel was within normal limits. The C-reactive protein was within normal limits at <0.5 mg/dL, and the erythrocyte sedimentation rate was 14 mm/h. Lumbar puncture was remarkable for an opening pressure of 21 cmH2O, and cerebral spinal fluid (CSF) profile revealed 74 nucleated cells/µL (40% neutrophils, 44% lymphocytes, 16% mononuclear cells), 0 erythrocytes/µL, protein of 86 mg/dL and glucose of 26 mg/dL. Initial diagnostic testing for a wide breadth of pathogens was negative, including plasma HIV-1 RNA, serum HIV fourth-generation antigen/antibody, urine histoplasma enzyme immunoassay, serum and CSF Coccidioides complement fixation and immunodiffusion, tuberculosis interferon-gamma release assay and CSF Mycobacterium tuberculosis complex polymerase chain reaction (PCR). CSF multiplex PCR panel was negative for all targets, including Escherichia coli K1, Haemophilus influenzae, Listeriamonocytogenes, Neisseria meningitidis, Streptococcus agalactiae, Streptococcus pneumoniae, cytomegalovirus, enterovirus, herpes simplex virus 1 and 2, human herpesvirus 6, human parechovirus, varicella zoster virus and Cryptococcus neoformans/gattii complex.
The diagnosis of tuberculosis meningitis was entertained, and the child was started on empiric dexamethasone, rifampin, isoniazid, pyrazinamide and streptomycin. She was additionally started on empiric ceftriaxone and fluconazole. On the morning of hospital day 2, she had another self-limited event characterized by slurred speech and right-sided facial droop. On hospital day 3, further diagnostic studies on blood and CSF revealed the correct diagnosis.
On hospital day 3, the CSF culture grew a yeast that was ultimately identified as Cryptococcus neoformans by PCR. CSF cryptococcal antigen titer was positive at 1:2, and serum cryptococcal antigen testing was also found to be positive with a titer of 1:128. Empiric antituberculosis therapy was discontinued, and the child was started on induction therapy for cryptococcal meningitis: amphotericin B liposome (5 mg/kg intravenous every 24 hours) and 5-fluorocytosine (100 mg/kg/d per os div q6h) for a 2-week course. The child completed a 2-week taper of corticosteroids. After completion of induction therapy, a repeat lumbar puncture demonstrated an opening pressure of 16 cmH2O, an undetectable cryptococcal antigen titer, and no growth on fungal culture. Repeat CSF profile showed 17 nucleated cells/µL (27% neutrophils, 62% lymphocytes, 11% mononuclear cells), 0 erythrocytes/µL, protein of 58 mg/dL and glucose of 34 mg/dL. The child was transitioned to consolidation therapy of oral high-dose fluconazole (12 mg/kg/d) before discharge from the hospital. Since discharge from the hospital, she has remained asymptomatic. Repeat magnetic resonance imaging revealed improvement in prior areas of enhancement, and magnetic resonance angiography demonstrated decreased narrowing of the affected intracranial arteries. A thorough evaluation of her immune system including testing for quantitative immunoglobulins, neutrophil oxidative burst, natural killer cell quantification and function, complement levels, T- and B-cell quantification, lymphocyte proliferation to antigens and mitogens panel, primary immunodeficiency gene panel (Invitae, San Francisco, CA), Streptococcus pneumoniae and Haemophilus influenza titers, Mendelian susceptibility to mycobacterial disease (Medical College of Wisconsin, Milwaukee, WI) and T- and B-cell clonality screening did not reveal an underlying immunologic disorder.
Cryptococcus is an encapsulated yeast with the potential to cause infection in both immunocompromised and immunocompetent hosts. Cryptococcus neoformans is typically associated with trees and with pigeon or other bird droppings, and Cryptococcus gattii has been associated with trees, particularly eucalyptus. Classically, cryptococcal meningitis is considered an AIDS-defining condition in HIV patients, and up to 30% of patients with AIDS will develop cryptococcal disease.1 Among non-HIV-infected patients, up to 60% of patients are transplant recipients.2 That said, a 2010 study describing the epidemiology of cryptococcal disease in children in the United States found up to 21% of affected children did not have a described immunodeficiency.3
Cryptococcal meningoencephalitis (CME) is typically indolent and characterized on imaging by leptomeningeal and subarachnoid findings.4 Up to 80% of patients will present with increased intracranial pressure, and over 20% patients will have focal deficits.5 Patients typically have normal to moderate CSF pleocytosis.5 India ink test on CSF can be a useful diagnostic tool but has limited sensitivity and potential for both false-positive and false-negative results. The sensitivity of CSF fungal culture can be as high as 90%, but CSF cryptococcal antigen has greater than 90% sensitivity.6,7 Furthermore, cryptococcal antigen titers in the CSF can be helpful as a prognostic tool, with higher titers suggesting poorer outcomes.8 Complications include hydrocephalus, immune reconstitution inflammatory syndrome, and the development of Central Nervous System cryptococcomas. Vasculitis in the setting of CME has been described but is uncommon. Just 13% of adults with CME have radiographic evidence of infarct, but when neurovascular injury is discovered, mortality can climb upward of 30%, and lasting neurologic disability can be greater than 50%.9,10 Given the rarity of this condition, the incidence and outcomes among children have not been described.
Treatment for CME typically involves a 2-week induction course with amphotericin B and 5-fluorocytosine. If the initial opening pressure is high (≥25 cmH2O), lumbar punctures are repeated daily until intracranial hypertension has been stabilized for >2 days.7 In severe cases, a CSF drain and/or shunt may be clinically indicated.4,7,11 If the fungal culture remains positive at the 2-week mark or if the patient remains symptomatic, induction is continued with serial lumbar punctures at 2-week intervals until symptoms resolve and CSF culture is negative. After completing induction therapy, immunocompetent patients are generally transitioned to consolidation dosing of fluconazole (10–12 mg/kg/d) for at least 8 weeks, followed by a 6- to 12-month period of maintenance dosing (6 mg/kg/d). The role of corticosteroids is unclear; however, given the theorized mechanism of immune-mediated complex deposition contributing to vasculopathy, some experts do suggest treatment once vasculitis is discovered.9,10
In conclusion, we have described a case of cryptococcal basilar meningoencephalitis in a 5-year-old girl whose presenting symptoms were headaches and presumed transient ischemic attacks secondary to CME-associated vasculitis. She did not have any known risk factors for the acquisition of CME and, after extensive evaluation of her immune system, was found to be immunocompetent. This case highlights the importance of considering cryptococcus in the differential diagnosis in both immunocompetent and immunocompromised children with either focal neurologic deficits or basilar meningitis.
1. Bicanic T, Harrison TS. Cryptococcal meningitis. Br Med Bull. 2004;72:99–118.
2. Vilchez RA, Fung J, Kusne S. Cryptococcosis in organ transplant recipients: an overview. Am J Transplant. 2002;2:575–580.
3. Joshi NS, Fisher BT, Prasad PA, et al. Epidemiology of cryptococcal infection in hospitalized children. Pediatr Infect Dis J. 2010;29:e91–e95.
4. Huang KY, Huang YC, Hung IJ, et al. Cryptococcosis in nonhuman immunodeficiency virus-infected children. Pediatr Neurol. 2010;42:267–270.
5. Abadi J, Nachman S, Kressel AB, et al. Cryptococcosis in children with AIDS. Clin Infect Dis. 1999;28:309–313.
6. Antinori S, Radice A, Galimberti L, et al. The role of cryptococcal antigen assay in diagnosis and monitoring of cryptococcal meningitis. J Clin Microbiol. 2005;43:5828–5829.
7. Perfect JR, Dismukes WE, Dromer F, et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the infectious diseases society of america. Clin Infect Dis. 2010;50:291–322.
8. Powderly WG, Cloud GA, Dismukes WE, et al. Measurement of cryptococcal antigen in serum and cerebrospinal fluid: value in the management of AIDS-associated cryptococcal meningitis. Clin Infect Dis. 1994;18:789–792.
9. Mishra AK, Arvind VH, Muliyil D, et al. Cerebrovascular injury in cryptococcal meningitis. Int J Stroke. 2018;13:57–65.
10. Oberman DZ. Central nervous system vasculitis for Cryptococcosis in an immunocompetent patient. 2018;6:75.
11. Chen SC, Slavin MA, Heath CH, et al.; Australia and New Zealand Mycoses Interest Group (ANZMIG)-Cryptococcus Study. Clinical manifestations of Cryptococcus
gattii infection: determinants of neurological sequelae and death. Clin Infect Dis. 2012;55:789–798.