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New Approaches to Dealing with PML, Meningitis, and Encephalitis


doi: 10.1097/01.NT.0000349803.61605.9b
Departments: Best of the Field

New inroads in efforts to manage progressive multifocal leukoencephaly (PML) and tuberculous meningitis, as well as to diagnose and manage subtypes of encephalitis, were the focus of several papers deemed most noteworthy this year by neuroinfectious disease experts Joseph R. Berger, MD, Ruth L. Works Professor and chairman of the department of neurology at University of Kentucky College of Medicine in Lexington, and Karen L. Roos, MD, John and Nancy Nelson Professor of Neurology at the University of Indiana in Indianapolis.

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In a paper published Dec. 5 online ahead of the Jan. 20 print edition of Virology, investigators suggest that in vitro expansion of JC-virus (JCV)-specific cytotoxic T-lymphocytes (CTL) by peptide-loading autologous dendritic cells (DC) may be a strategy for clinical immunotherapy of PML.

Lead author Angela Marzocchetti, MD, of the department of neurology and Division of Viral Pathogenesis at Beth Israel Deaconess Medical Center of Harvard Medical School, and colleagues wrote that the potential benefits of such immunotherapy are substantial, since a persistent JCV-specific CTL response could limit the extent of damage induced by JC-virus (the cause of PML), and eventually have an impact on survival.

The cellular immune response mediated by JCV-specific CTL has been shown to prevent progression of PML, and the authors thought that a treatment to enhance this response against JCV would help patients with PML.

Such immunotherapy could be performed using the dendritic cells (DC) of the patient pulsed in vitro with JCV peptides, then re-injected in the patient where they would stimulate the patient's own lymphocytes to fight against JCV (DC-based immunotherapy). Another approach would be to stimulate in vitro the patient's own lymphocytes with JCV peptides, then re-inject the lymphocytes into the patient (autologous transfer therapy).

The authors compared these two methods side by side in vitro: DC-based stimulation of JCV-specific T cells or direct peptide stimulation of lymphocytes from blood samples of 20 JCV seropositive subjects, including six with PML, four HIV-positive subjects, and 10 healthy controls. In 13 of 15 responders, JCV peptide-loaded DC elicited a more potent CTL expansion compared with direct peptide stimulation of lymphocytes in vitro. These results suggest that in most cases, DC-based immunotherapy would elicit a more potent immune response against JCV in patients than autologous transfer of T cells.



The senior study author Igor Koralnik, MD, and his team are now working on the clinical development of DC-based immunotherapy for PML. Dr. Koralnik is director of the HIV/Neurology Center at Beth Israel Deaconess Medical Center and associate professor of neurology at Harvard Medical School.

Dr. Berger said that the article “demonstrates the importance of the dendritic cell in mounting an effective cell-mediated response to JCV.” He noted that previous investigators demonstrated that brain perivascular dendritic cells are wiped out for a long period of time following the administration of natalizumab. “The elimination of dendritic cells may substantially contribute to the appearance of PML in natalizumab-treated patients with multiple sclerosis. However, it is not the only mechanism by which this or other drugs may predispose to the development of disease,” he said.

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Are corticosteroids effective for tuberculous meningitis, a condition that affects CNS meninges, and is associated with high mortality and disability in survivors? That is the focus of an extensive literature review in the January 2009 Cochrane Review.

Although corticosteroids have been used as adjunctive therapy to antituberculous drugs to improve outcome, their role has been controversial. The review included seven randomized controlled trials with a total of 1,140 patients with clinically diagnosed tuberculous meningitis — randomized to a corticosteroid plus antituberculous treatment or antituberculous treatment alone.



Overall, corticosteroids reduced the risk of death by 22 percent. Three trials with data on disabling neurological deficits showed that corticosteroids reduced the risk of death or disabling neurological deficit by 18 percent.

Adverse events were mild and treatable and included gastrointestinal bleeding, bacterial and fungal infections, and hyperglycemia. The lead author Kameshwar Prasad, MBBS, MD, professor of neurology at the All India Institute of Medical Sciences in New Delhi, concluded that corticosteroids should be used routinely in HIV-negative patients with tuberculous meningitis to reduce death and disabling neurological deficits. The weight of evidence remains unconvincing for use of corticosteroids in tuberculous meningitis patients who are HIV-positive, however.

“This paper addresses an important and controversial topic — whether corticosteroids should be used in tuberculous meningitis. The weight of the evidence supports their use in HIV-negative patients. Whether they should be used in HIV-positive patients remains controversial,” Dr. Berger said.

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Encephalitis can be caused by many different organisms and the diagnosis can be difficult to establish. Most pathogens known to cause encephalitis are viruses, bacteria, or protozoa, but the etiology of encephalitis often remains uncertain even after extensive testing. Another challenge is to determine the relevance of an infectious agent identified outside the CNS that may exacerbate neurological manifestations. Once an infectious agent is identified, there may not be an established treatment.

“Encephalitis can be a frightening disease for neurologists, because many neurologists may be unaware of the appropriate tests for diagnosis, clinical clues to the different types of encephalitis, and how to treat the disease,” explained Dr. Roos.

To rectify the knowledge gap, Dr. Roos and other members of the Infectious Disease Society of America developed guidelines for differential diagnosis and management of encephalitis, which were published in the August 2008 issue of Clinical Infectious Disease.

Table 5 in the article will be most helpful to “neurologists in the trenches,” Dr. Roos said. The co-authors wrestled with this table for many hours to come up with a comprehensive listing of the whole panoply of agents that cause encephalitis, as well as the epidemiology, clinical features, and treatment recommendations for known subtypes.

Important new findings published in these guidelines pertain to Epstein-Barr virus, human herpes virus 6 (HHV6), West Nile virus, and St. Louis virus. Dr. Roos pointed out that acyclovir should not be used to treat Epstein-Barr virus, although many neurologists use this drug. “We don't know how to treat it. The disease gets better on its own,” she commented.

“HHV6 is a hot topic,” Dr. Roos continued. Most neurologists treat HHV6 with either acyclovir or foscarnet. The guidelines explain that both agents should be used simultaneously to treat HHV6. “If a patient is on one of these agents, we recommend adding the other so the patient is on two agents,” she said.

Ribavarin is not recommended for treatment of West Nile virus, although some neurologists may be using it. The guidelines state that there is no treatment for this type of encephalitis other than supportive care.

Most neurologists treat St. Louis encephalitis with supportive care. According to the new guidelines, interferon 2 alpha should be considered. Dr. Roos noted that this recommendation is based on expert opinion and case reports, since there are no randomized controlled trials.

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Dr. Berger singled out a case review of acute meningoencephalitis due to HIV-1 virus as offering important information for the neurologist. The review was published online in the November 2008 issue of the Journal of Neurovirology.

“Acute meningoencephalitis occurring in a patient with an acute HIV infection or after discontinuation or interruption of antriretroviral therapy [ART] is an under-recognized, but sometimes life-threatening entity. This review sheds some light on the clinical manifestations of these patients and the clinical course,” he said.

The review centered on 13 cases of severe meningitis (seven women and six men) caused by HIV-1 occurring during primary infection (10 cases) or after antiretroviral treatment (ART) interruption (three cases). Sexual transmission was the risk factor for HIV-1 infection in all 13 cases.

The most frequent systemic symptoms were fever (12 cases), headache (nine cases), and gastrointestinal symptoms (eight cases). Neurologic symptoms included focal signs (seven patients, 53.8 percent), confusion (six patients, 46.2 percent), and agitation (five patients, 38.5 percent).

The most striking focal signs were ataxia, unilateral Bell palsy, and paresthesia. CSF was clear with normal glucose levels in all cases. Cranial CT was normal in seven patients. Of eight patients who had brain MRI, five had normal scans, and three showed a different abnormality. ART was initiated in 11 patients. All 13 patients recovered without neurologic sequelae.

The need for ART is not well established, wrote Sara Villar del Saz, MD, of the Hospital Universitari Vall d'Hebron, Automonous University of Barcelona, Spain, and colleagues, but the evidence from this case series suggest it may have benefit for this rare and potentially lethal type of encephalitis.

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Marzocchetti A, Lima A, Koralnik IJ, et al. Efficient in vitro expansion of JC virus-specific CD8* T-cell responses by JCV peptide-stimulated dendritic cells from patients with progressive multifocal leukoencephalopathy. Virology 2009;383(2): 173–177. E-pub 2008 Dec 5.
    Prasad K, Singh MB. Corticosteroids for managing tuberculous meningitis. Cochrane Database Syst Rev 2009;61:100–107.
      Tunkel AR, Glaser CA, Whitley RJ, et al., for the Infectious Diseases Society of America. The management of encephalitis: Clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis 2008;47(3):303–327.
        Villar del Saz S, Sued O, Ribera E, et al. Acute meningoencephalitis due to human immunodeficiency virus type 1 infection in 13 patients: Clinical description and follow-up. J Neurovirol 2008;14:474–479.
          ©2009 American Academy of Neurology