Protocol Proving Effective in Fungal Meningitis Outbreak Patients

Pauline Anderson

November 14, 2012

Clinicians are getting a kind of crash course in how to best manage patients affected by the recent fungal meningitis outbreak linked to injections of a contaminated steroid.

Early evidence suggests that the culprit organism (Exserohilum) may be angioinvasive, that stroke is a concern, and that initial therapy with intravenous (IV) voriconazole is probably warranted. However, recovery can be slow and patients need to be closely monitored.

Doctors at Carilion Roanoke Memorial Hospital in Virginia, who were pressed into action to tackle emergency department (ED) cases with little guidance, shared their observations and lessons learned in an article published online November 12 in Annals of Internal Medicine.

Because patients may have traveled or visited other parts of the country, it's important that clinicians nationwide become aware of this outbreak of fungal infections that affect the central nervous system, study author, Ekta Bansal, MD, an infectious disease fellow at the hospital, told Medscape Medical News. "If patients present with headache and other complaints, clinicians should ask about their epidural steroid injection (ESI) history."

She stressed that patients can have had a variable response to treatment and that management of these fungal meningitis cases requires a multidisciplinary approach.

Protocol Developed

In the wake of the outbreak that has been linked to injections of methylprednisolone acetate, a steroid used to treat back and joint pain, the hospital established a dedicated "hotline" on October 2 and developed a protocol for evaluating patients presenting to the ED.

Of 172 patients who presented to the ED, the majority (85%) did so between October 4 and 23, and the mean time from the steroid injection to onset of symptoms was 23 days.

Most (n = 131) patients who had received an ESI from either of the 2 facilities that used contaminated products and had a headache, stiff neck, or pain at the site of the injection received a lumbar puncture (LP), usually after brain MRI.

Of these, 25 (12 women and 13 men) met the meningitis definition of a cerebrospinal fluid level greater than 10 white blood cells per mL. They ranged in age from 32 to 92 years (mean, 63.2 years).

The current report is based on these 25 cases but also includes information on 2 other patients who were transferred from another facility after sustaining a stroke, died soon thereafter, and were diagnosed retrospectively.

Of 27 total cases, 8 had a positive polymerase chain reaction result for Exserohilum, 13 had negative results, and 6 were awaiting results at the time the article was written.

All 25 patients who presented at the hospital's ED were alert and oriented on admission. Almost all reported headache, which they described as the worst they ever had.

The next most common symptom was difficulty finding words (72%). Although this symptom improved somewhat in some cases, "our next plan is to refer patients for cognitive therapy to see if that helps," said Dr. Bansal.

The next most common signs were nausea/vomiting (68%), fever (64%), and neck stiffness (60%). About a third (32%) had urinary retention. The number of signs and symptoms per patient ranged from 2 to 6.

Arachnoiditis Incidence

There appeared to be a higher than usual incidence of arachnoiditis, an inflammation of the membrane surrounding the central nervous system nerves, with signs of cauda equina syndrome, a loss of function of the lumbar plexus, perhaps due to the anatomic location of the ESI procedure.

"Almost 50% of our patients have inflammation at the site of the injection that we are seeing as arachnoiditis," said Dr. Bansal.

Brain MRI was performed for 23 patients; findings were normal in 14 and abnormal in 9. The most common abnormal finding was enhancement of the leptomeninges in 7 patients. Two patients had hemorrhagic infarcts, and 4 had evidence of ventriculitis.

All patients with meningitis began receiving IV voriconazole at a dose of 6 mg/kg every 12 hours. Three patients sustained a stroke while receiving this treatment, suggesting that the Exserohilum organism is angioinvasive, said Dr. Bansal. Physicians continue to do repeat LPs and imaging in these patients, she added.

Of the patients who began IV voriconazole, 15 continue taking that drug. Ten patients were switched to IV amphotericin B because of worsening clinical signs and symptoms.

Some patients have gone on to oral voriconazole.

"When the presenting complaints, headache being the most common, get better and the repeat LP shows improvement in white counts, that's when we make a decision to switch to the oral and then we observe the patient in hospital for few days before we discharge them," said Dr. Bansal.

According to the article, 8 patients have been discharged and as of November 14, more have been treated and discharged. Fifteen patients are currently being monitored as outpatients.

All discharged patients are being seen in a specially established clinic within the infectious disease unit. They continue to receive oral voriconazole with weekly follow-up. Repeat LPs are planned for every 3 to 4 weeks until findings are negative.

Vigilance Important

In an accompanying commentary, Shmuel Shoham, MD, and Kieren A. Marr, MD, Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, Maryland, discussed some of the pressing concerns related to the fungal meningitis outbreak.

It's important, stressed Dr. Shoham in an interview with Medscape Medical News, to be vigilant about patients who may have been exposed to the contaminated steroid and to maintain that vigilance.

"Fungal organisms can take awhile to incubate and to become manifest in a clinically evident way."

It's also important to get exposed patients to contact their clinician if they notice anything suspicious, such as new-onset or worsening headaches, that might signal an infection, and for doctors to take patients' concerns very seriously, he said.

Although all treatment decisions should involve patients, the discussion of the risks and benefits of an LP is all the more important in the wake of this outbreak.

"The information we have that we're working with is not nearly as robust as with infections of other entities," said Dr. Shoham. "We don't have a database of 10,000 patients who have been treated for this thing, so we should be honest with the patient and families about what we know and what we don't know, and the possible side effects of lumbar puncture."

Neuropsychiatric Toxicity

Although rare, these adverse effects can include an increase in liver aminotransferases and neuropsychiatric toxicity.

"I've seen people hallucinate on this drug; I've seen people have extraordinarily vivid dreams on it; people can get funny lights in their eyes, although it doesn't mean that if you get this medication, you're going to get toxicity and most people don't," he said.

In lower-risk situations, it's probably not advisable to use prophylaxis antifungal therapy, said Dr. Shoham.

"I would say as a general policy that the benefits are not worth the risks in this group," because of possible adverse effects and because voriconazole carries a relatively high risk for drug interactions.

Such interactions are a particular concern among the elderly, said Dr. Shoham.

In making treatment decisions for the elderly, it's important to remember that because they're more likely to be taking other medications, there's more of a concern for drug interaction.

Also, because their system tends to break down medications at a relatively slow rate, they may have higher levels, which may put them at an elevated risk for adverse effects, said Dr. Shoham.

The meningitis outbreak represents an active learning opportunity for clinicians, said Dr. Shoham.

"I've treated many, many patients with fungal infections, but this particular fungal infection is extraordinarily rare to begin with, and as a cause of meningitis I think it's exceedingly rare. It's a really active learning curve; we definitely know more now than we knew a month ago."

Several key questions about the natural history of this infection remain to be answered, though, said Dr. Shoham.

"For example, we don't know how long to treat it and we don't know when it's okay to stop treating it."

He's not sure if all the patients who are going to get an infection have been identified because there are so many variables. It could be that those patients who got the steroid near, but not right at, the meninges will take longer to develop an infection.

The study authors and Dr. Shoham have disclosed no relevant financial relationships.

Ann Intern Med. Published online November 12, 2012. Full text Commentary