In the fall of 2012, as we finalized this issue of CONTINUUM, an unprecedented outbreak of fungal meningitis occurred that was caused by contaminated preservative-free methylprednisolone acetate solution from the New England Compounding Center used in epidural steroid injections in thousands of patients. The predominant pathogen was found to be Exserohilum rostratum (a black mold). Aspergillus fumigatus and Cladosporium were identified, as well. At the time of writing, all of the patients who have become sick received epidural steroid injections with methylprednisolone from one of three contaminated methylprednisolone lots. Seventeen thousand five hundred vials of methylprednisolone from these contaminated lots were distributed to 75 facilities in 23 states.1
Neurologists are knowledgeable about the treatment and complications of fungal meningitis. In this issue of CONTINUUM, Drs Zunt and Baldwin review the diagnosis and treatment of meningitis due to Cryptococcus neoformans, Histoplasma capsulatum, Coccidioides immitis, and Aspergillus fumigatus in the article “Chronic and Subacute Meningitis.” The complications of fungal meningitis—most notably hydrocephalus, increased intracranial pressure, and stroke—are difficult to manage. Shunt obstructions in CNS mold infections are common, requiring multiple shunt revisions and associated morbidity.
Fungal meningitis causes “subacute meningitis,” which by definition is headache and low-grade fever of 4 weeks' or greater duration caused by inflammation that evolves over weeks to months.
As of November 5, 2012, the US Centers for Disease Control and Prevention (CDC) has not recommended antifungal prophylaxis or lumbar puncture for asymptomatic patients who received epidural steroid injections. The CDC has recommended the initiation of IV voriconazole, 6 mg/kg every 12 hours, for symptomatic patients with meningitis or parameningeal infections who received contaminated epidural steroid injections until the etiology of the meningitis or parameningeal infection can be determined. In addition, the CDC has recommended consideration of IV liposomal amphotericin B, 7.5 mg/kg/day, in addition to voriconazole, in patients with severe disease and in those who do not improve or have progressive disease with voriconazole monotherapy.2
As the number of deaths continues to rise, both neurologists and their patients hope for the ability to identify CNS infection or parameningeal infection prior to the onset of symptoms. The index case of Exserohilum rostratum, reported by Lyons and colleagues,3 had abnormal enhancement on MRI in cervical paraspinal muscles at the epidural steroid injection site suggestive of possible infected fluid collection. Two serologic tests are available for invasive fungal disease. The Aspergillus galactomannan assay is sensitive and specific for invasive infection due to Aspergillus species, while the [beta]-D-glucan assay is sensitive for invasive fungal disease.4 CSF analysis is either normal or abnormal. In meningitis caused by a fungus or mold, there is a CSF pleocytosis, a decreased glucose concentration, and an increased protein concentration. In a parameningeal infection, CSF pleocytosis and an increased protein concentration are characteristic. CSF should also be sent for fungal smear and culture, the [beta]-D- glucan assay, and the Aspergillus galactomannan assay. CSF should not be obtained at the level of the neuroaxis where the epidural steroid injections were given because of the risk of spinal osteomyelitis or epidural abscess at the site of injection. If serology or CSF analysis is abnormal, imaging of the level of the spine where the epidural injection was performed is indicated. These recommendations may not lead to early detection, but the only alternative is watchful waiting, and as the number of deaths continues to increase, a more proactive approach may be indicated.
1. Centers for Disease Control and Prevention (CDC). Multistate outbreak of fungal infection associated with injection of methylprednisolone acetate solution from a single compounding pharmacy—United States, 2012. MMWR Morb Mortal Wkly Rep 2012; 61 (41): 839–842.
3. Lyons JL, Gireesh ED, Trivedi JB, et al.. Fatal Exserohilum
meningitis and central nervous system vasculitis after cervical epidural methylprednisolone injection [published online ahead of print October 17, 2012]. Ann Intern Med. In press.
4. Cuétara MS, Alhambra A, Moragues MD, et al.. Detection of (1->3)-[beta]-D-glucan as an adjunct to diagnosis in a mixed population with uncommon proven invasive fungal diseases or with an unusual clinical presentation. Clin Vaccine Immunol 2009; 16 (3): 423–426.