Case History Shows How Quickly Fungal Meningitis Kills

Megan Brooks

October 19, 2012

The clinical course of 1 of the index cases of the widening fungal meningitis outbreak linked to tainted steroid injection shows the aggressive, angioinvasive nature of Exserohilum species, the fungus implicated in most cases to date, say clinicians from Johns Hopkins University School of Medicine in Baltimore, Maryland.

In a letter published online October 17 in Annals of Internal Medicine, Jennifer L. Lyons, MD, and colleagues provide details about the clinical care, deterioration, and ultimately death a woman with fulminant Exserohilum species meningitis due to an epidural cervical injection with contaminated, preservative-free methylprednisolone acetate.

This case "illustrates the need for rapid recognition and treatment" of Exserohilum meningitis "in an effort to limit morbidity and mortality," they write.

Meanwhile, a report online today in the New England Journal of Medicine (NEJM) from April C. Pettit, MD, MPH, and colleagues at Vanderbilt University School of Medicine in Nashville, Tennessee, provides details of the index case for the fungal meningitis outbreak.

To date, federal health officials have reports of 271 cases (including 21 deaths) in 16 states of fungal meningitis linked to contaminated methylprednisolone acetate from the New England Compounding Center (NECC) in Framingham, Massachusetts.

Yesterday, officials with the Centers for Disease Control and Prevention (CDC) and the US Food and Drug Administration (FDA) said they have confirmed the presence of E rostratum in unopened medication vials of preservative-free methylprednisolone acetate (80 mg/mL) from 1 of the 3 implicated lots from NECC (Lot #08102012@51, BUD 2/6/2013).

The laboratory confirmation further links steroid injections from these lots from NECC to the multistate outbreak of fungal meningitis and joint infections. Testing on the other 2 implicated lots of methylprednisolone acetate and other NECC injectable medications continues, the CDC said on its Web site.

First Steroid Injection

In the case published in Annals of Internal Medicine, the 51-year-old patient, who had 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 August 31, 2012.

It was her first steroid injection for neck pain.

She had no history of immune compromise or trauma and was not taking any long-term medications. Physical examination and computed tomography of the head were normal, and she was discharged. No lumbar puncture was performed.

The woman returned to the emergency department the following 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 her first day in the hospital was normal. By day 3, she remained afebrile but developed slurred speech, right hemiparesis, left facial droop, and anisocoria, prompting a second MRI, which showed a punctate focus of diffusion restriction in the pons, the team says.

Lumbar puncture revealed a 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, and white blood cell count of 850 × 109 cells/L (84% neutrophils and 15% lymphocytes); results of Gram stain and bacterial culture were negative.

On day 4, treatment with acyclovir, cefepime, vancomycin, doxycycline, and methylprednisolone was initiated; however, she continued to deteriorate and developed dysphagia, leading to endotracheal intubation.

A third MRI showed multifocal areas of restricted diffusion in the pons, midbrain, and cerebellum and diffuse leptomeningeal enhancement.

Rapid Deterioration

Repeated 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 white blood cell count of 72 × 109 cells/L (64% neutrophils, 4% lymphocytes, and 4% monocytes).

Polymerase chain reaction testing of CSF was negative for herpes simplex virus, varicella zoster virus, Epstein-Barr virus, cytomegalovirus, and West Nile virus, as were cryptococcal and histoplasma antigens and CSF bacterial culture.

Repeated MRI of the brain 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.

The clinicians say the patient's health continued to deteriorate rapidly over the next several days, until she died 10 days later. Exserohilum species was reported in the CSF on the day she died.

Autopsy revealed a grossly necrotic brainstem, and microscopic examination showed angioinvasive, septate fungal hyphae associated with diffuse vasculitis and hemorrhagic infarction in the brain and spinal cord.

In their report, Dr. Lyons and colleagues note that human disease caused by Exserohilum species is "rare," although most pathologically confirmed cases in the ongoing outbreak of fungal meningitis were caused by this fungus.

"Intriguing" First Case

In the new NEJM report discussing the index case, researchers report that the man, who was his 50s, had a history of degenerative lumbar disc and joint disease and presented with headache and neck pain that had become progressively worse over the course of 8 days. Four weeks before presentation, he had received the latest in a series of epidural steroid injections of methylprednisolone.

On the basis of initial evaluation, the patient began receiving vancomycin, ceftriaxone, ampicillin, and glucocorticoids and was admitted to the hospital. Routine bacterial cultures of the blood and CSF were negative, and the glucocorticoids were stopped. The patient's symptoms improved with antimicrobial therapy, and he was sent home to complete the course of vancomycin and ceftriaxone for presumed community-acquired meningitis.

He presented 1 week after discharge with worsening symptoms and was hospitalized. On day 7 the microbiology laboratory confirmed Aspergillus fumigatus. The patient died on hospital day 22.

"What's intriguing about this case report is that the mold causing meningitis was reported to be Aspergillus fumigatus, an organism that has not been detected in any of the subsequent 200-plus cases," write the authors of a review article also published today in NEJM, entitled, "Fungal Infections Associated with Contaminated Methylprednisolone Injections—Preliminary Report."

Although the primary pathogen appears to be E rostratum, "it is possible that other pathogens could emerge and it remains a mystery as to why the index case is the sole case in which A. fumigatus was detected," write Carol Kauffman, MD, from the Veterans Affairs Ann Arbor Healthcare System in Michigan and colleagues.

They say it is "encouraging" that clinically apparent disease has developed in only a small percentage of exposed patients.

The CDC is providing regular clinical guidance updates (and new updates) on the fungal meningitis outbreak and the clinician's role.