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ILLUSTRATIVE CASE Not All Aseptic Meningitis Is Created Equal Sameer Pathare, MDa,b,c

CASE A 16-year-old Chinese American boy was brought to the emergency department by his parents after 1 day of headache, neck pain, fever, and fatigue. He denied any cough, vomiting, diarrhea, or weight loss, but he did report having an erythematous, papular skin rash along his hairline for the past 6 weeks. A dermatologist evaluated the rash and diagnosed impetigo. A trial of topical bacitracin and oral cephalexin temporarily improved the rash. He is a native of southern California, was previously healthy, was fully immunized, had no previous hospitalizations, and had no pertinent family history. It is of note that he had no ill contacts, had no recent illnesses, and denied travel outside of southern California. On examination, the patient had a temperature of 38.9°C, a heart rate of 78 beats per minute, a blood pressure reading of 110/46 mm Hg, a respiratory rate of 16 breaths per minute, and an oxygen saturation of 96% on room air. He was not ill-appearing. His lungs were clear to auscultation, and his heart sounds suggested a regular rate and rhythm with no murmurs. His abdomen was soft, nontender, nondistended, and without hepatosplenomegaly. On neurologic examination, he was alert and oriented with no focal findings; specifically, he had no nuchal rigidity or photophobia. His skin examination was notable for crusted excoriated papules along the anterior hairline and a solitary lesion on the right forearm. Laboratory evaluation of peripheral blood revealed a white blood cell (WBC) count of 11.3 k/mL, with a differential of 86.2% neutrophils, 7.2% lymphocytes, 4.8% monocytes, and 1.1% eosinophils; a hemoglobin level of 12 g/dL; a platelet concentration of 285 k/mL; a C-reactive peptide level of 19.9 mg/L; a erythrocyte sedimentation rate of 27 mm/hour, a sodium concentration of 139 mmol/L; a potassium level of 3.8 mmol/L; a chloride level of 105 mmol/L; a bicarbonate level of 27 mmol/L; a blood urea nitrogen concentration of 12 mg/dL; a creatinine level of 0.9 mg/dL; a glucose measurement of 98 mg/dL; an aspartate aminotransferase level of 23 U/L; an alanine aminotransferase concentration of 23 U/L; and a total bilirubin reading of 0.5 mg/dL. Noncontrast computed tomography of the head revealed normal results. A lumbar puncture (LP) was performed in the emergency department in response to the patient’s persistent headaches. Cerebrospinal fluid (CSF) analysis revealed a WBC count of 187/mL, with a differential of 24% neutrophils, 40% lymphocytes, 33% monocytes, and 3% eosinophils; a red blood cell count of 13/mL; a protein level of 127 mg/dL; and a glucose reading of 47 mg/dL. A Gram-stain revealed many WBCs

www.hospitalpediatrics.org a CHOC Children’s DOI:https://doi.org/10.1542/hpeds.2016-0184 Specialists Hospitalist Copyright © 2017 by the American Academy of Pediatrics Division, Children’s Hospital of Orange Address correspondence to Sameer Pathare MD, CHOC CS Hospitalist Division, CHOC Children’s Hospital, 1201 West La Veta Ave, Orange, County, Orange, CA 92868. E-mail: [email protected] California; bDepartment HOSPITAL PEDIATRICS (ISSN Numbers: Print, 2154-1663; Online, 2154-1671). of Pediatrics, School of Medicine, University of FINANCIAL DISCLOSURE: The author has indicated he has no financial relationships relevant to this article to disclose. California, Irvine, Irvine, FUNDING: California; and No external funding. c Department of POTENTIAL CONFLICT OF INTEREST: The author has indicated he has no potential conflicts of interest to disclose. Pediatrics, Geisel School of Medicine, Dartmouth Dr Pathare conceptualized and designed the case report, drafted the initial manuscript, conducted the initial analyses, critically College, Hanover, New reviewed and revised the manuscript, approved the final manuscript as submitted, and agrees to be accountable for all aspects of Hampshire the work.

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Downloaded from www.aappublications.org/news by guest on September 27, 2021 but no organisms. Enterovirus (EV) with increased incidence in the summer a glucose reading of ,20 mg/dL. An and herpes simplex virus (HSV) months. West Nile virus has a similar infectious disease consultation was polymerase chain reaction tests were pattern, peaking in the summer when requested in response to the persistently fi sent, and, while awaiting culture mosquitoes are plentiful. HSV can abnormal CSF ndings. cause either aseptic meningitis or results, the patient was started on meningoencephalitis. Mycobacterium Question: What is the differential ceftriaxone (2 g every 12 hours) and tuberculosis, although unlikely, is also a diagnosis for chronic meningitis vancomycin (1 g every 6 hours) in possibility but would only be expected in with elevated protein and fi response to the CSF ndings of this age group if immunosuppression were hypoglycorrhachia? elevated WBCs, elevated protein, and present. low glucose. He was admitted to the Discussion In this patient, the original LP findings The persistence of inflammatory changes hospital, and, within 24 hours, his revealed a modest elevation of WBCs coupled with the additional findings of headache improved and his fever with lymphocyte predominance. The elevated protein and depressed glucose in resolved. His blood and CSF bacterial presence of eosinophils suggests parasitic the CSF narrows the differential diagnosis cultures revealed negative results. or fungal etiologies. Parasites can include considerably. Most cases of chronic His polymerase chain reaction tests amoeba and helminths, such as those meningitis can be divided into infectious, were negative for both EV and HSV. causing neurocysticercosis.1 Fungal autoimmune, and neoplastic etiologies, with possibilities include those present in the He was back to his neurologic the infectious etiology being most common.2 soil of the southern California deserts, such baseline, and he was discharged A brain abscess is a consideration, with the as Coccidioides imitus, and those not from the hospital on hospital day 2 members of the Streptococcus anginosus typically found in southern California, such because of the improvement in his group (Streptococcus intermedius, as Histoplasma capsulatum and symptoms. S anginosus, and Streptococcus Blastomyces dermatitidis. constellatus) increasingly recognized as Question: What is the differential 3–5 CASE CONTINUATION pathogens. However, a brain MRI with diagnosis for a teenager with The patient continued to have persistent normal results that do not reveal a contrast- aseptic meningitis? headaches, neck pain, and intermittent enhancing lesion effectively rules out a vomiting for 2 weeks at home, which brain abscess. In addition, pretreated Discussion prompted his return for medical attention. bacterial meningitis needs to be considered In this age group, the differential diagnosis There was concern about the possibility of if antibiotics were given before the original for acute aseptic meningitis is extensive. increased intracranial pressure and a LP, which was not the case with this patient. 1 According to Seehusen et al, cell count subacute central nervous system infection. Brucella and Leptospira are also rare 6–8 and differential alone cannot distinguish A magnetic resonance imaging (MRI) scan causes of chronic menigitis. between bacterial and nonbacterial of the brain with contrast was performed, Other more likely possibilities include meningitis. Of patients with bacterial the results of which were normal, without mycobacterial and fungal infections (see . 3 meningitis, 87% will have CSF WBCs 1000/mm , hydrocephalus or brain abscess. Because of Table 1). Tuberculous meningitis is usually , 3 whereas having 100 CSF WBCs/mm is the persistence of severe headaches and confined to children ,2 years of age or to 1 more common with viral meningitis. the development of photophobia, a repeat immunocompromised patients and often fi Lymphocytosis is nonspeci candcanbeseen LP was performed. The repeat CSF test presents with disseminated disease. The in viral, fungal, and tuberculous meningitis. revealed a WBC count of 892/mL, with a presence of eosinophilia (defined as Viral etiologies of meningitis include the differential of 33% neutrophils, .10 eosinophils/mm3)1 is unusual and nonpolio EVs, which are ubiquitous and 47% lymphocytes, 5% eosinophils, and 10% warrants further evaluation for fungal or present year-round in southern California, monocytes; a protein level of 218 mg/dL; and parasitic etiologies. Cryptococcus

TABLE 1 CSF Parameters for Tuberculous and Fungal Meningitis Organism CSF WBC Count Differential Glucose Protein CSF Testing M tuberculosis Increased Mononuclear Decreased Increased AFB smear, PCR and AFB culture C neoformans Increased or normal Mononuclear Decreased Increased India ink, cryptococcal antigen, fungal culture C immitus Increased or normal Early neutrophilic, lymphocytic, or Decreased Increased Complement ﬁxation serum antibody, fungal eosinophilic culture H capsulatum Increased Mononuclear Decreased Increased Histoplasma antigen, fungal culture B dermatitidis Increased Early neutrophilic or lymphocytic Decreased Increased Fungal culture Adapted from Zunt JR, Baldwin KJ. Chronic and subacute meningitis. Continuum (Minneap Minn). 2012;18(6):1290–1318. AFB, acid-fast bacilli; PCR, polymerase chain reaction.

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Downloaded from www.aappublications.org/news by guest on September 27, 2021 neoformans is the most common central He required serial LPs to help manage his Pediatric patients hospitalized with nervous system fungal infection in headache symptoms, each time with coccidioidomycosis often have severe and immunocompromised patients, particularly transient improvement. His opening sometimes life-threatening disease. In a in those with HIV. Endemic mycoses such as pressure was measured on subsequent case series of 33 hospitalized pediatric Histoplasma, Blastomyces, and Coccidioides LPs and was .40 cm water (normal: patients in central California, 6% had may all present with modestly elevated ,20 cm water10).Acetazolamide therapy meningitis.14 When discussing disseminated WBCs, elevated protein, and low glucose, was initiated to help manage his disease, the percentage of meningitis rises even in healthy patients. Furthermore, increased intracranial pressure. Because to 30% to 50%, and hydrocephalus parasites such as cestodes, trematodes, of the need for continued LPs to manage subsequently develops in 20% to 50% of and protozoans can infect the central or his intracranial pressure and headache, patients with coccidioidal meningitis. For peripheral nervous system, but are less a ventriculoperitoneal shunt was placed. patients with increased intracranial common.9 Further history revealed that he most pressure at the time of diagnosis, the likely had exposure to Coccidioides in the Infectious Disease Society of America CASE RESOLUTION California high desert at an outdoor recommends medical therapy, imaging fi A puri ed protein derivative skin test was shopping mall ∼1 to 2 months before (including brain MRI scans with and without placed to further evaluate for tuberculous onset of his symptoms. After a 3-week contrast), and repeated LPs as initial meningitis and revealed negative results at hospitalization, he has been doing well as management. They also recommend 48 hours. Because chronic skin lesions can an outpatient for well over 1 year on oral obtaining a neurosurgical consultation for also be seen in disseminated fungal fluconazole therapy. ventriculoperitoneal shunt placement in disease, a skin punch biopsy was obtained cases in which increased intracranial ’ from the solitary lesion on the patients CONCLUSIONS pressure does not resolve.15 In a study by forearm. Coccidioides titers by complement C immitus and C posadasii are endemic McCarty et al,14 3% of patients with fi xation were sent to a reference laboratory, fungi found in the southwestern United coccidioidal meningitis required shunt fl and uconazole was started empirically. States, northern Mexico, and some areas of placement.12 Coccidioidal meningitis The pathology results from a skin biopsy South America, causing the disease treatment involves 4 weeks of induction revealed mild to moderate chronic active commonly known as “Valley Fever.” The with high-dose fluconazole, whereas fl in ammation with a necrotizing granuloma. fungi are found in warm, sandy soil, in refractory coccidioidal meningitis treatment An acid-fast bacilli stain yielded negative climates with hot, arid summers and mild regimens also include intrathecal results, but the results of a periodic acid- rainfall. The dimorphic fungi grow as amphotericin B. All initial treatment Schiff stain were positive for fungal hyphae in the soil. Spores (arthroconidia) regimens are followed by daily azole infection, with 1 intact spherule suggestive are stable and can remain viable for maintenance treatment for life.9,15 of Coccidioides (Fig 1). many years. Infection is through inhalation In summary, aseptic meningitis is a benign ’ The patients CSF cultures grew fungus at of the aerosolized spores. When inhaled self-limited disease, particularly when it is fi day 5, which was eventually identi ed as into the lungs after soil disruption by of viral etiology. Patients who are not Coccidioides immitus/posadasii. His serum wind, construction, or cultivation, the improving as expected require a broader Coccidioides serology test by complement fungus initiates growth by forming a evaluation and approach, particularly fi xation revealed positive results at a spherule. The spherule expands and during the winter season, when viral 1:128 ratio, whereas his quantitative serum undergoes nuclear division, producing etiologies are less common. A complete immunoglobulins were at normal levels and endospores. When spherules rupture the evaluation should include routine CSF his HIV enzyme-linked immunosorbent assay endospores are released, each is capable of studies, such as WBC count with differential, was nonreactive. developing into new spherules, which can tests for protein and glucose levels, 11 disseminate hematogenously to any organ. cultures, and tests of opening pressure. As Most coccidioidal infections are this case reveals, the presence of elevated asymptomatic or cause a self-limited WBCs, elevated protein, low glucose, and disease with mild respiratory infection; eosinophils in the CSF of a patient who therefore, a delay in diagnosis is common. resides or has traveled to the southwestern However, dissemination can occur more United States should lead to the commonly in Filipinos, African Americans, consideration of Coccidioides infection as pregnant women, and immunocompromised the diagnosis. An infectious disease patients (especially those with HIV or on consultation should be obtained when the immunosuppressive therapy).12,13 CSF parameters are not consistent with Disseminated diseases include pneumonia, those expected for a self-limited disease. soft tissue infection, osteomyelitis, and Opening pressure on CSF is not routinely FIGURE 1 Intact spherule on skin biopsy. meningitis. performed in pediatrics; however, it may be

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Downloaded from www.aappublications.org/news by guest on September 27, 2021 valuable in the evaluation and management 3. Maliyil J, Caire W, Nair R, Bridges D. protozoans. Semin Neurol. 2005;25(3): of coccidioidal meningitis. When Splenic abscess and multiple brain 262–277 disseminated Coccidioides is suspected, abscesses caused by Streptococcus 10. Rangel-Castilla L, Gopinath S, Robertson diagnostic testing of Coccidioides serum intermedius in a young healthy man. CS. Management of intracranial antibodies, fungal culture, CSF Coccidioides Proc Bayl Univ Med Cent. 2011;24(3): hypertension [published correction fi – titers by complement xation, opening 195 199 appears in Neurol Clin. 2008;26(3):xvii]. pressure, and biopsy of any skin lesions 4. Carpenter J, Stapleton S, Holliman R. Neurol Clin. 2008;26(2):521–541, x should be performed. Retrospective analysis of 49 cases of 11. Nguyen C, Barker BM, Hoover S, et al. LEARNING POINTS brain abscess and review of the Recent advances in our understanding literature. Eur J Clin Microbiol Infect Dis. • A chronic skin rash may be a subtle of the environmental, epidemiological, 2007;26(1):1–11 finding of systemic disease. immunological, and clinical dimensions • Elevated protein, low glucose, and 5. Deutschmann MW, Livingstone D, Cho JJ, of coccidioidomycosis. Clin Microbiol – eosinophilia in the spinal fluid may Vanderkooi OG, Brookes JT. The Rev. 2013;26(3):505 525 fi indicate fungal or parasitic disease and signi cance of Streptococcus anginosus 12. Mathisen G, Shelub A, Truong J, Wigen C. warrant further evaluation, including an group in intracranial complications of Coccidioidal meningitis: clinical infectious disease consultation. pediatric rhinosinusitis. JAMA presentation and management in the Otolaryngol Head Neck Surg. 2013; fl • CSF opening pressures are helpful in the uconazole era. Medicine (Baltimore). 139(2):157–160 – management of fungal meningitis. 2010;89(5):251 284 6. Bodur H, Erbay A, Akinci E, Colpan A, • Fungal meningitis may lead to prolonged 13. Ruddy BE, Mayer AP, Ko MG, et al. Cevik MA, Balaban N. Neurobrucellosis in increased intracranial pressure, often Coccidioidomycosis in African Americans. an endemic area of brucellosis. Scand J requiring the placement of a Mayo Clin Proc. 2011;86(1):63–69 Infect Dis. 2003;35(2):94–97 ventriculoperitoneal shunt. 14. McCarty JM, Demetral LC, Dabrowski L, 7. Mantur BG, Akki AS, Mangalgi SS, Patil • Coccidioidal meningitis requires azole Kahal AK, Bowser AM, Hahn JE. Pediatric SV, Gobbur RH, Peerapur BV. Childhood treatment for life. coccidioidomycosis in central California: – brucellosis a microbiological, a retrospective case series. Clin Infect REFERENCES epidemiological and clinical study. Dis. 2013;56(11):1579–1585 J Trop Pediatr. 2004;50(3):153–157 1. Seehusen DA, Reeves MM, Fomin DA. 15. Galgiani JN, Ampel NM, Blair JE, et al. fl Cerebrospinal uid analysis. Am Fam 8. Wilhelm CS, Marra CM. Chronic Executive summary: 2016 Infectious – Physician. 2003;68(6):1103 1108 meningitis. Semin Neurol. 1992;12(3): Diseases Society of America (IDSA) – 2. Baldwin KJ, Zunt JR. Evaluation and 234 247 clinical practice guideline for the treatment of chronic meningitis. 9. Walker MD, Zunt JR. Neuroparasitic treatment of coccidioidomycosis. Clin Neurohospitalist. 2014;4(4):185–195 infections: cestodes, trematodes, and Infect Dis. 2016;63(6):717–722

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Downloaded from www.aappublications.org/news by guest on September 27, 2021 Not All Aseptic Meningitis Is Created Equal Sameer Pathare Hospital Pediatrics 2017;7;765 DOI: 10.1542/hpeds.2016-0184 originally published online November 30, 2017;

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