Jennifer L. Lyons, MD; Elakkat D. Gireesh, MD; Julie B. Trivedi, MD; W. Robert Bell, MD; Deanna Cettomai, MD; Bryan R. Smith, MD; Sarah Karram, MD; Tiffany Chang, MD; Laura Tochen, MD; Sean X. Zhang, MD, PhD; Chad M. McCall, MD, PhD; David T. Pearce, BS; Karen C. Carroll, MD; Li Chen, MD, PhD; John N. Ratchford, MD, MSc; Daniel M. Harrison, MD; Lyle W. Ostrow, MD, PhD; Robert D. Stevens, MD
Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M12-2577.
This article was published at www.annals.org on 17 October 2012.
Lyons J., Gireesh E., Trivedi J., Bell W., Cettomai D., Smith B., Karram S., Chang T., Tochen L., Zhang S., McCall C., Pearce D., Carroll K., Chen L., Ratchford J., Harrison D., Ostrow L., Stevens R.; Fatal Exserohilum Meningitis and Central Nervous System Vasculitis After Cervical Epidural Methylprednisolone Injection. Ann Intern Med. 2012;157:835-836. doi: 10.7326/0003-4819-158-1-201212040-00557
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Published: Ann Intern Med. 2012;157(11):835-836.
Background: Between 21 May and 26 September 2012, about 14 000 patients received spinal epidural injections with contaminated methylprednisolone from a compounding pharmacy, resulting in a multistate outbreak of fungal meningitis (1). The etiologic agent has since been identified predominantly as Exserohilum species, a dematiaceous fungus, although a case of Aspergillus fumigatus was reported (1). The clinical and pathologic spectra of central nervous system disease due to Exserohilum remain largely unknown.
Objective: To describe one of the index cases of fulminant Exserohilum species meningitis due to an epidural cervical injection with contaminated, preservative-free methylprednisolone acetate.
Methods and Findings: A 51-year-old woman with a history of neck pain, hyperlipidemia, headaches, and fibromyalgia presented to a local emergency department with new occipital headache radiating to the face 1 week after a cervical epidural steroid injection on 31 August 2012 (Chen L, Lyons JL. Personal communication.). She had not received injections previously, had no history of immune compromise or trauma, and was not taking any long-term medications. Physical examination and unenhanced head computed tomography were normal, and she was discharged. No lumbar puncture was performed. She returned the next day with diplopia, vertigo, nausea, and ataxia and was hospitalized. Physical examination was notable only for hoarseness and decreased tendon reflexes; routine serum chemistry and blood counts were normal, and she had no fever. Magnetic resonance imaging (MRI) of the brain on hospital day 1 was normal. By day 3, she remained afebrile but developed slurred speech, right hemiparesis, left facial droop, and anisocoria, prompting repeated MRI. Results showed a punctate focus of diffusion restriction in the pons. Lumbar puncture had an opening pressure of 34 cm H2O, glucose level of 1.998 mmol/L (36 mg/dL) (serum glucose level of 5.828 mmol/L [105 mg/dL]), total protein level of 153 mg/dL, leukocyte count of 850 × 109 cells/L (84% neutrophils and 15% lymphocytes), and negative Gram stain and bacterial culture. Treatment with acyclovir, cefepime, vancomycin, doxycycline, and methylprednisolone was initiated; however, she continued to deteriorate and developed dysphagia, leading to endotracheal intubation and transfer to our tertiary care center on day 4 (Smith BR, Ostrow LW. Personal communication.). Magnetic resonance imaging on transfer showed multifocal areas of restricted diffusion in the pons, midbrain, and cerebellum and diffuse leptomeningeal enhancement (Figure, A and C). Repeat lumbar puncture on day 7 showed a glucose level of 2.719 mmol/L (49 mg/dL) (serum glucose level of 8.436 mmol/L [152 mg/dL]), protein level of 104 mg/dL, and leukocyte count of 72 × 109 cells/L (64% neutrophils, 4% lymphocytes, and 4% monocytes). Polymerase chain reaction testing of cerebrospinal fluid for herpes simplex virus, varicella zoster virus, Epstein–Barr virus, cytomegalovirus, and West Nile virus was negative, as were cryptococcal and histoplasma antigens and cerebrospinal fluid bacterial culture. Repeat MRI of the brain (Figure, B, D, and E) showed new restricted diffusion in the left anterior thalamus, progression of brainstem infarction and edema, and interval development of ventriculomegaly, prompting placement of an externalized ventricular drain that did not result in clinical improvement. Magnetic resonance imaging of the neck (Figure, F and G) showed inflammation and possible fluid collection in the soft tissues at the injection site, although follow-up ultrasonography did not corroborate fluid amenable to tap. On day 9, neurologic examination progressed to absent pupillary, corneal, and gag reflexes, and liposomal amphotericin B was added empirically. On day 10, all brainstem reflexes were lost, and death from neurologic criteria was pronounced. Exserohilum species was reported in the cerebrospinal fluid the same day. Autopsy revealed a grossly necrotic brainstem, and microscopic examination showed angioinvasive, septate fungal hyphae associated with diffuse vasculitis (Figure, H) and hemorrhagic infarction in the brain and spinal cord.
Brain and neck MRI and histopathologic findings from a patient with Exserohilum leptomeningitis and stroke.
Axial diffusion-weighted imaging from hospital days 4 (A) and 7 (B) shows progression of pontine infarction (arrows). Axial T2-weighted fluid attenuated inversion recovery imaging from hospital days 4 (C) and 7 (D) similarly shows disease progression as indicated by increasing hyperintensity in the midbrain (arrows) and interval development of ventriculomegaly secondary to brainstem edema (asterisks). Additional infarctions with similar evolution were located in the medulla and cerebellar hemispheres (not shown). Coronal T1 imaging after the administration of intravenous gadolinium on hospital day 7 (E) shows diffuse leptomeningeal enhancement (arrows) and ventriculomegaly (asterisks). Axial T2-weighted short tau inversion recovery imaging (F) and T1-weighted imaging after the administration of intravenous gadolinium (G) of the neck show hyperintensity and abnormal enhancement in cervical paraspinal muscles at the epidural steroid injection site, suggesting subcutaneous edema and possible infected fluid collection (arrows). Postmortem hematoxylin–eosin stain of the right middle cerebral artery (H) shows abundant septate fungal hyphae penetrating the vessel (arrowheads) with concomitant acute inflammatory response. MRI = magnetic resonance imaging.
Discussion: Human disease caused by Exserohilum species is rare, and fulminant meningitis has not been reported (2). To date, most pathologically confirmed cases of meningitis reported in the 2012 outbreak were caused by Exserohilum (1). In 2002, 5 cases of fungal meningitis complicating epidural steroid injection occurring 34 to 152 days after exposure were linked to contamination with Exophiala species at a compounding pharmacy, resulting in 1 death (3, 4).
Conclusion: This case shows the aggressive, angioinvasive nature of Exserohilum species with an incubation time that is seemingly shorter than that of Exophiala, albeit to date unknown, and illustrates the need for rapid recognition and treatment (5) of this possible procedural complication to limit morbidity and mortality.
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