IDSA committee proposes guidelines for managing encephalitis

December 2005

A committee formed by the IDSA is developing guidelines for the management of encephalitis. Allan R. Tunkel, MD, PhD, professor of internal medicine at Drexel University College of Medicine in Philadelphia, presented a preliminary report of the guidelines at the 43^rd Annual Meeting of the Infectious Diseases Society of America, held in San Francisco.

Tunkel stressed the importance of recognizing epidemiologic and clinical clues that suggest a specific etiology of encephalitis. “I can’t overemphasize the importance of these clues, because the epidemiology that can be established in the history and physical exam will guide the work-up,” he said.

One clue is the season of the year. If a patient, for example, presents in August, physicians should consider agents that are transmitted by mosquitoes and ticks.

Geographic locale is another clue. It is important to understand local disease prevalence and to determine whether outbreaks of other agents have recently occurred, Tunkel said. Additionally, physicians should ask about travel, especially international travel. If the patient has traveled recently, the physician will want to find out that area’s local disease prevalence as well.

Other clues are recreation and occupation. Understanding what a patient does during his or her free time and for a living can help a physician determine the cause of encephalitis.

“It is also important to understand the immune status of the patient. Certainly, if the patient is HIV positive or has other immune defects, you need to consider a whole host of other organisms. Also, determine whether the patient has received transfusions or undergone transplantation,” he said.

Clinical clues include rash, respiratory tract findings and neurological findings.

General diagnostic studies

In patients with suspected encephalitis, blood cultures are usually performed to look for bacteria or fungi. If the patient has any type of rash, it should be unroofed and cultured. The direct fluorescent antibody test should be considered to help diagnose infection caused by herpes viruses, Tunkel said. If an enterovirus or measles virus is suspected, throat and stool cultures are also appropriate.

All skin lesions require a biopsy, he said. Serum immunoglobulin M (IgM) and enzyme-linked immunosorbent assays may be helpful for diagnosing specific viral causes of encephalitis. If reactivation disease is a possibility, serum IgG may be helpful, he added.

Neurodiagnostic tests

“An important neurodiagnostic test is neuroimaging, such as a CT with contrast or an MRI with gadolinium. MRI is certainly the diagnostic modality of choice,” he said.

Electroencephalography is a nonspecific indicator of cerebral dysfunction. Additionally, cerebrospinal fluid (CSF) analysis is very important. In most cases of viral encephalitis, there will be a mononuclear pleocytosis, elevated protein and normal glucose. However, there are exceptions in patients with encephalitis caused by some viruses.

“It is important to note that CSF analysis in some causes of encephalitis (specifically that caused by herpes simplex virus) can be normal in 5% to 10% of patients on first sampling of CSF. Cultures for bacteria and analysis for specific IgM antibodies are very important. IgM antibodies do not regularly cross the blood-brain barrier, so their presence against a specific etiologic agent would indicate that this is a disease that is within the central nervous system,” he said.

In diseases such as herpes simplex encephalitis, there have been reports where an initial CSF polymerase chain reaction (PCR) was negative and then a repeat CSF PCR analysis was positive. So, if the diagnosis is suspected and the CSF PCR is negative, physicians may want to repeat the analysis within three to seven days.

“Brain biopsy is rarely used today, but it can be considered in patients who deteriorate even after they’ve been treated with acyclovir,” he said.

When choosing an empiric therapy in patients with encephalitis, acyclovir is the top choice because herpes simplex encephalitis is one of the most prevalent treatable causes of viral encephalitis in the United States.

“Other potential agents should be chosen based on the patient’s presentation. If the patient has pleocytosis, particularly if it is neutrophilic, you may need to also consider the possibility that the patient has bacterial meningitis,” Tunkel said. “For suspicion of rickettsial organisms, it is appropriate to add doxycycline to the regimen while you are waiting for the results of your important diagnostic tests.”

Specific therapy

Once the etiology of encephalitis is established, physicians will need to determine which therapy to administer or continue.

For herpes simplex encephalitis, many studies have shown that acyclovir is the therapeutic agent of choice. In adults with normal renal function, the dose is 10 mg/kg every 8 hours, and in neonates, the dose is 20 mg/kg every 8 hours. The use of acyclovir at these dosages in neonates has lowered mortality to about 5%. Patients should become PCR negative before stopping therapy with acyclovir.

“Where there are fewer data for varicella zoster virus encephalitis, acyclovir is certainly the best bet we have. We also don’t have good data for treatment of cytomegalovirus (CMV) encephalitis. Some have suggested using combination therapy with ganciclovir and foscarnet (Foscavir, AstraZeneca), and it is probably the best we have to offer right now. However, the data are not very good, and there have been cases where bone marrow transplant patients received prophylactic combination therapy and still developed CMV encephalitis,” he said.

“For encephalitis caused by the enteroviruses, we cannot yet use pleconaril (ViroPharma Inc.) because it is not FDA approved. It is available on a compassionate-use basis, and it is recommended for use in patients who have very serious enteroviral disease,” Tunkel said.

There are data against the use of interferon and steroids for the treatment of Japanese encephalitis. For influenza, which causes encephalopathy more often than encephalitis, Tunkel said he would use an appropriate anti-influenza medication. He noted, however, that data to support this do not exist.

Some data have suggested that ribavirin may be associated with deleterious effects in patients with West Nile virus encephalitis, he said, and hyperimmune globulin is currently being studied. For diseases caused by Listeria, ampicillin and gentamicin should be used. Many physicians use azithromycin or a fluoroquinolone to treat mycoplasma. The recommendations will include doxycycline for diseases caused by Rickettsia.

These guidelines are currently in draft form, and the committee expects them to be finalized soon.

For more information:

• Tunkel AR. Encephalitis. Symposium #67. Presented at the 43rd Annual Meeting of the Infectious Diseases Society of America. Oct. 6-9, 2005. San Francisco.