Two-year-old With Hydrocephalus

CASE PRESENTATION A fully vaccinated, including the Bacille-Calmette-Guerin vaccine, 2-year-old female presented to an Emergency Department with nighttime headaches, dizziness, photophobia, nystagmus, and altered gait for several days. For 3 consecutive nights, the patient had woken in the middle of the night with headaches and dizziness episodes. Her mother describes her arms splayed out and eyes moving side-to-side. At 12 months, the patient had similar episodes of nystagmus while living in Mexico. At that time, an electroencephalogram was normal; neuroimaging was not done. On hospital admission of her current illness, her physical exam was notable for an irritable toddler. Her vitals revealed a temperature of 36.1 °C, heart rate of 125 beats/min, respiratory rate of 32 breaths/min, and a blood pressure of 125/85 mm Hg. Her neurologic exam revealed a normal gaze without nystagmus, intact cranial nerves 2–12, 5/5 strength in the upper and lower extremities, and gait exam with intermittent episodes of postural instability and stumbling while playing in the exam room. The rest of the physical exam was completely normal. Complete blood count was notable for white blood cell count of 12.6 k/cu mm, hemoglobin of 11.6 g/dL, and platelet count of 411 k/cu mm. Serum electrolytes and liver enzymes were within normal limits. Her C-reactive protein was <5 mg/L (ref range <10.0) and her erythrocyte sedimentation rate (ESR) was 24 mm/h. Computed tomography of the head showed moderate dilation of bilateral ventricles without evidence of an obstructing lesion. There was also symmetric hypodensities within the white matter potentially reflective of transependymal edema/acute hydrocephalus. A magnetic resonance imaging (MRI) of her brain and spine revealed ventriculomegaly with patent flow, extensive periventricular T2 hyperintensity, basilar predominant diffuse leptomeningeal enhancement, and spinal arachnoiditis (Fig. 1). An external ventricular drain (EVD) was emergently placed and cerebrospinal fluid (CSF) studies demonstrated 24 white blood cells per high power field with a lymphocytic predominance, glucose 63 mg/dL, protein of 62 mg/dL, negative Gram stain, negative leukemia/lymphoma flow cytometry markers and a negative meningitis-encephalitis multiplex polymerase chain reaction panel. Following her head imaging and EVD placement, an infectious diseases consultation was requested. Additional history revealed that, three months before presentation, the patient had emigrated from Tijuana, Mexico to Oregon. The family denied animal contacts, sick contacts, contacts living with HIV, or known tuberculosis (TB) contacts. The patient had lived in a crowded group environment during the immigration process from Mexico. The patient’s immunizations were up-to-date for age. Based on her exposure history and neuroimaging findings, the patient was started on an empiric treatment regimen for the most likely etiology. Diagnostic testing from her CSF and serum later revealed the diagnosis.FIGURE 1.: (A) Enlarged bilateral lateral and third ventricles with adjacent T2/FLAIR hyperintense signal is concerning for a component of acute hydrocephalus. (B) On high resolution BFFE images, there is narrowing although likely patent cerebral aqueduct (arrow). (C) There is extensive abnormal FLAIR hyperintensity and enhancement along the leptomeningeal surfaces of the brain (arrows). (D) Leptomeningeal enhancement with a basilar predominance, especially within the suprasellar and basilar cisterns (arrows).DENOUEMENT Given her MRI findings of basilar predominant diffuse leptomeningeal enhancement, lymphocytic pleocytosis in her CSF, and potential risk for TB exposure during the immigration process from Mexico, empiric treatment for TB meningitis was initiated with isoniazid, rifampin, pyrazinamide, and levofloxacin. Corticosteroid treatment was held, as oncologic disease was not completely ruled out. Her TB evaluation later yielded two negative interferon gamma release assay blood tests, three negative gastric aspirate acid fast bacillus stains, a negative CSF acid fast bacillus stain, two negative CSF Mycobacterium TB polymerase chain reactions and a negative CSF adenosine deaminase assay. While continuing TB therapy, the patient underwent ventriculoperitoneal (VP) shunt placement for permanent CSF diversion and a right frontal brain biopsy for further work-up. Surgical pathology of brain tissue demonstrated histiocytes thought to be secondary to infection versus postoperative inflammation from the EVD procedure. Several days after the biopsy, serum studies resulted positive for Histoplasma antibodies via complement fixation with titers of 1:32 and 1:128 for yeast and mycelial forms, respectively. Fungal CSF studies had not been performed before VP shunt placement. A lumbar puncture was performed, and the CSF was negative for Histoplasma antibodies via complement fixation and Histoplasma Galactomannan antigen via enzyme immunoassay (EIA). Urine Histoplasma antigen was also negative. Given conflicting fungal assays, our infectious disease group consulted with the Miravista Diagnostics mycology reference laboratory (Indianapolis, IN). They recommended sending additional fungal studies including Histoplasma antigen via EIA from the CSF and serum and Histoplasma IgM and IgG via EIA from the serum to their laboratory. Given improved neurologic exam after VP shunt placement, the patient was discharged on empiric TB treatment while evaluation for invasive fungal disease was ongoing. After hospital discharge, Histoplasma antigen via EIA from Miravista Diagnostics resulted weakly positive from both the CSF (0.68 ng/mL) and serum (0.39 ng/mL). Serum Histoplasma IgM (38.7 EU) and IgG (13.7 EU) antibodies were also detected. With serologic and antigenic Histoplasma positivity in the serum and CSF, and negative TB diagnostics, TB therapy was discontinued and the patient was readmitted for intravenous liposomal amphotericin B induction (5 mg/kg/day). Of note, chest and abdominal imaging showed no evidence of disseminated histoplasmosis. Repeat CSF evaluation after 2 weeks of amphotericin therapy revealed a decreasing Histoplasma antigen to 0.4 ng/mL, negative fungal CSF culture and brain MRI demonstrated resolution of leptomeningeal enhancement. Given clinical and radiographic improvement, her antifungal treatment was transitioned to oral itraconazole (titrated to goal trough of 2 mcg/mL), and the patient was discharged home. Even in outbreak settings, symptomatic histoplasmosis is rare in pediatrics and most children experience asymptomatic or mild infections. Disseminated disease is the most common clinical phenotype in symptomatic patients, accounting for 30–80% of cases in some reviews, often in an immunocompromised host.1 CNS involvement is present 10–48% of the time in reported pediatric disseminated cases.1 Isolated CNS disease in an immunocompetent child is rare, with our review yielding only 9 previous cases in the literature (Table 1).2–9 The majority of these cases occurred in South America, with the exception of two cases occurring in the US Ohio River Valley. This aligns with the traditional epidemiology of histoplasmosis being intensely endemic in the Ohio and Mississippi River Valleys of the US, parts of Mexico and much of Central and South America. However, factors such as climate change, deforestation, soil movement and human migration have led to wider geographic distribution of histoplasmosis infections without travel to these endemic regions; cases have been reported in California, Arizona, Idaho, Montana and New York.10 In Mexico, where our patient was born, most cases (an estimated 112–325 per year) occur primarily in the Central and South-Eastern states of Veracruz, Oaxaca, Campeche, Tabasco and Chiapas. These areas are geographically distant from Tijuana, where our patient was born and lived prior to emigration. Notably, the low incidence is likely an underestimation given limited testing capabilities and lack of surveillance programs in these areas.10 TABLE 1. - Previously Reported Cases of Isolated CNS Histoplasmosis in Immunocompetent Children Study Country Age/Sex Chief Complaint Exposure Diagnostic Test Treatment Outcome Bellin et al2 Puerto Rico 4/M LE weakness, vision loss Unknown Serum Histo serology by CF, CSF fungal culture, skin test IV and IT Amp-B (2 months) Lost to follow-up Gasparetto et al3 Brazil 13/M Vision loss, hearing loss, HA, emesis, hx of seizures Raised chickens Surgical biopsy of histoplasmosis nodule Fluconazole Survived Schestatsky et al4 Brazil 3/M HA, nuchal rigidity, fever, CN palsy, AMS, ataxia Unknown Surgical biopsy of lesion at autopsy None Deceased Schestatsky et al4 Brazil 15/M HA, nuchal rigidity Unknown CSF and serum Histo serology by immunodiffusion Amp-B (8 weeks), Fluconazole (1 year) Survived Lizarazo et al5 Colombia 10/M Left sided paresthesias, dysarthria, vertical nystagmus Raised chickens Serum Histo serology by immunodiffusion and CF Amp-B (6 weeks), Fluconazole (13 months) Survived Threlkeld et al6 USA (KY) 13/F HA, AMS, vomiting, neck and back pain, hearing loss, slurred speech, lip numbness Unknown CSF Histo serology by CF Amp-B (5 weeks), Itraconazole (1 year) Survived Schuster et al7 USA (TN) 6/M HA, emesis, slurred speech Chicken coop CSF fungal Culture Amp-B (5 weeks), Itraconazole (11 months) Survived Estebana et al8 Argentina 12/F HA, dysconjugate gaze, fever Unknown Serum and CSF Histo serology by counterimmunoelectrophoresis and immunodiffusion, CSF fungal culture Amp-B (6 weeks), Voriconazole (1 year) Survived de Brum et al9 Brazil 5/F HA, emesis Unknown Surgical biopsy of cerebral tissue Amp-B, Itraconazole (1 year) Survived Our case Mexico 2/F HA, dizziness, photophobia, nystagmus, ataxia Unknown Serum Histo serology by CF, CSF and serum Histo antigen via EIA Amp-B, itraconazole (ongoing) Survived AMS, indicates altered mental status; CF, complement fixation; CN, cranial nerve; HA, headache; IT, intrathecal; IV, intravenous; LE, lower extremity. Our case demonstrates that, although rare, histoplasmosis can cause isolated CNS infection without dissemination in healthy children. Additionally, histoplasmosis should be considered when clinically appropriate, including in geographic areas not traditionally thought to be endemic. ACKNOWLEDGMENTS The authors thank Dr. L. Joseph Wheat of Miravista Diagnostics for his invaluable assistance in the workup, interpretation of critical lab values, and support of the manuscript in this case.