Human herpesvirus 6 encephalomyelitis.

To the Editor: Denes et al. (1) reports successful treatment of human herpesvirus 6 (HHV-6) encephalomyelitis. The patient was an immuno-competent young woman whose symptoms were fever, urinary retention, blurred vision, quadriparesis, bilateral papillitis, and optic neuritis. Magnetic resonance imaging (MRI) showed multiple lesions on the spinal cord white matter and the left thalamus, and the cerebral spinal fluid (CSF) showed inflammation. The patient was treated with acyclovir for 3 days, high-dose methylprednisolone for 5 days, cidofovir for 1 day, and ganciclovir for 15 days, starting on day 23 of hospitalization. By establishing a relationship between antiviral drug doses, serial determinations of HHV-6 DNA by polymerase chain reaction (PCR) in CSF, and neurologic improvement, Denes et al. concluded that antiherpesvirus drugs led to her recovery.

This case fits well in the spectrum of acute disseminated encephalomyelitis (ADEM), an inflammatory demyelinating disease of the central nervous systems of children and young adults, which occur in close temporal relationship with several infectious illnesses and immunizations (2-6). The disease has particular predilection to the optic nerves, spinal cord, brainstem, basal ganglia, and cerebral and cerebellar hemispheres. Maximal neurologic deficits are reached within several days, and resolution takes weeks or months. The condition is typically monophasic, but relapses have been reported (7). Histologic multifocal areas of inflammation and demyelinization are Ibund. In the pathogenesis of ADEM, an initial injury caused by an infectious agent, followed by a secondary autoimmune response, has been postulated, and animal models have provided experimental support; both CD4 and CD8 T cells have been implicated in a secondary autoimmune response (6). Despite the lack of controlled studies, corticosteroids are widely used to treat ADEM and high-dose methylprednisolone is the drug of choice (3,4). The largest series of ADEM in adults included 40 patients with a mean follow-up period of 38 months. The patients were given a standardized treatment regimen of methylprednisolone, 500 mg daily intravenously for 5 days, with no additional therapy if they recovered completely. In patients with persistent neurologic deficits, the initial intravenous therapy was followed by a regimen of oral methylprednisolone, which was slowly tapered over 4 to 6 weeks. In patients with no response to this therapy, or whose condition had deteriorated during therapy, cyclophosphamide was given to seven patients, and immunoglobulin was given to one patient. Thirty-eight of 40 patients improved during the acute phase of the illness; in 7, symptoms completely resolved. One patient's condition remained unchanged and one patient died; no antiviral drugs were given (5).

The neurotropism of HHV-6 and that the CNS may be a site of viral persistence or latency are well recognized (8,9). On autopsy, evidence of fulminant encephalitis with HHV-6 DNA demonstrated by PCR, immuno-histochemical staining, or nucleic acid hybridization, confirms that HHV-6 causes acute CNS disease (8). Nevertheless, whether evidence of HHV-6 DNA in CSF demonstrated by PCR can be solely relied on is debatable. HHV-6 DNA was detected in the CSF of 41 (28.9%) of 142 children with a history of HHV-6 infection (9). HHV6-DNA was detected in the CSF of 47 (61%) of 77 children examined after primary HHV-6 infection. In the remaining 30 children (39%), HHV-6 DNA was detected in both peripheral blood mononuclear cells and CSF samples. HHV-6 variant A was detected more frequently in CSF than in specimens of other sites, which suggests that HHV-6A has greater neurotropism (10).

The role of HHV-6 in acute multifocal neurologic disease in immunocompetent adults requires additional observation, and its role in multiple sclerosis is in question. Much can be learned from careful study of patients (1).

I caution the casual reader who may conclude that using antiviral drugs against herpes viruses is recommended when acute mutlifocal neurologic disease clinically compatible with ADEM is indicated. High-dose IV methylprednisolone is the most utilized treatment, and the patient in the Denes et al. report was given it early in her hospital stay. The available evidence supports methylprednisolone as an essential drug in the management of ADEM.

Jose Luis Soto-Hernandez *

* Instituto Nacional de Neurologia Mexico, Mexico City, Mexico

References

(1.) Denes E, Magy L, Pradeau K, Alain S, Weinbreck E Ranger-Roguez S. Successful treatment of human herpesvirus 6 encephalomyelitis in an immunocompetent patient. Emerg Infect Dis. 2004;10:729-31.

(2.) Mader I, Stock KW, Ettlin T, Probst A. Acute disseminated eucephalomyelitis: MR and CT features. Am J Neuroradiol. 1996;17:104-9.

(3.) Hartung HP, Grossman Rt. ADEM: Distinct disease or part of the MS spectrum? Neurology. 2001;56:1257-60.

(4.) Tenembaum S, Chamoles N, Fejerman N. Acute disseminated encephalomyelitis a long-term follow-up study of 84 pediatric patients. Neurology. 2002;59:1224-31.

(5.) Schwarz S, Mohr A, Knauth M, Wildemann B, Storch-Hagenlocher B. Acute disseminated encephalomyelitis: a follow-up study of 40 adult patients. Neurology. 2001;56:1313-8.

(6.) Stave O, Zamvil SS. Pathogenesis, diagnosis, and treatment of acute disseminated encephalmnyelitis. Curr Opin Neural. 1999;12:395-401.

(7.) Cohen O, Steiner-Birmanns B, Biran I, Abramsky O, Honigman O, Steiner I. Recurrence of acute disseminated encephalomyelitis at the previously affected brain site. Arch Neural. 2001;58:797-801.

(8.) Braun DK, Dominguez (3, Pellet PE. Human herpesvirus 6. Clin Microbiol Rev. 1997; 10:521-67.

(9.) Caserta MT, Hall CB, Schnabel K, McIntyre K, Long C, Costanzo M, et al. Neuroinvasion and persistence of human herpesvirus 6 in children. J Infect Dis. 1994;170:1586-9

(10). Hall CB, Caserta MT, Schnabel KC, Long C, Epstein LG. Insel RA, et al. Persistence of human herpesvirus 6 according to site and variant: possible greater neurotropism of variant A. Clin Infect Dis. 1998;26:32-7.

Address for correspondence: Jose Luis Soto-Hernandez, Instituto Nacional de Neurologia Mexico, Insurgentes Sur 3877, Tlalpan CP 14269, Mexico City, Mexico; fax: [phone]; email: joseluissotohernandez@ yahoo.com

In Reply: The disease that we reported (1) was encephalomyelitis induced by a human herpesvirus 6 (HHV-6) reactivation. Our aim was to emphasize that HHV-6 can cause such a disease, even when the patient is immunocompetent, and to urge physicians to search for it.

Implicating HHV-6 in the pathogenesis of neurologic manifestations in the reported case can be challenged, as suggested by Dr. Soto-Hernandez (2). Polymerase chain reaction (PCR) results must be interpreted cautiously, especially in cases that lack corroborating clinical evidence of infection. In our case, the diagnosis was made initially when HHV-6 was found in the patient's cerebral spinal fluid (CSF) by using PCR, by the absence of other cause, and by our experience: adult CSF is usually negative for HHV-6 by using PCR. Moreover, in our case, clinical symptoms and HHV-6 in the patient's CSF evolved in the same way. The neurologic tropism of HHV-6 is well known, and the main manifestation in adults is encephalitis, especially in an immunosuppressed context. Diagnosis is usually based on finding HHV-6 genetic material in the CSF (3,4), which has now replaced brain biopsy. Positive tissue results do not distinguish latent from productive infections when PCR-positive CSF indicates viral particle production in the central nervous system (CNS). In our case, the absence of brain tissue did not allow immunohistochemical staining or in situ hybridization. In the study by Caserta et al. (5), cited by Dr. Soto-Hernandez, HHV-6 PCR was positive in CSF and negative in peripheral blood mononuclear cells in 28.9% of children [less than or equal to] 3 years old with prior HHV-6 infection. These results provide evidence of HHV-6 persistence in the CNS; this phenomenon is now well recognized. Nevertheless, HHV-6 persistence after primary infection is quite different from reactivation in an immunocompetent adult. High-avidity anti-HHV-6 immunoglobulin G detected in the patient's serum when the symptoms started proved that our patient had been infected with HHV-6 previously.

We appreciate Dr. Soto-Hernandez's suggestion concerning acute demyelinating encephalomyelitis (ADEM) in our case. ADEM is an inflammatory demyelinating disease of the CNS, occurring mostly in children and rarely in young adults, soon after an infection or a vaccination. The disease is often associated with exanthema. A virus is often thought to be the cause, but viral symptoms are often not documented and rarely treated. ADEM may evolve into multiple sclerosis, and HHV-6 has been proposed as one of the causes of that condition (6). For example, multiple sclerosis developed in 14% of children and 35% of adults with ADEM in the study by Schwarz et al. (7).

Spontaneous improvement of ADEM is regularly reported; however, when treatment is needed, especially during the acute phase, steroid therapy is frequently used. In our case, corticosteroids did not affect the evolution of the patient's neurologic symptoms. Conversely, introducing the antiherpes drags (cidofovir and ganciclovir) was followed by improved clinical signs and negative results for HHV-6 in the CSF by PCR. Corticosteroids likely influence inflammation associated with ADEM, but if ADEM is the result of a viral infection with persistent viral replication, steroids might be deleterious, allowing an increase in viral replication (8,9).

In conclusion, we think that viruses, particularly HHV-6, should be considered in ADEM, even in immunocompetent patients. In case of a positive result, antiviral treatment must be given, eventually in association with corticosteroids. We cannot recommend using corticosteroids alone because of the risk of spreading the infection.

Eric Denes * and Sylvie Ranger-Rogez *

* Centre Hospitalier Universitaire, Dupuytren, Limoges, France

References

(1.) Denes E, Magy L, Pradeau K, Alain S, Weinbreck P, Ranger-Rogez S. Successful treatment of human herpesvirus type 6 encephalomyelitis in immunocompetent patient [letter]. Emerg Infect Dis. 2004; 10:729-31.

(2.) Soto-Hernandez JL. Human herpesvirus 6 encephalomyelitis [letter]. Emerg infect Dis. 2004;10:1700-1.

(3.) Yoshihara S, Kato R, Inoue T, Miyagawa H, Sashihara J, Kawakami M, et al. Successful treatment of life-threatening human herpesvirus-6 encephalitis with donor lymphocyte infusion in a patient who had undergone human leukocyte antigen-haploidentical nonmyeloablative stem cell transplantation. Transplantation. 2004;77:835-8.

(4.) Wainwright MS, Martin PL, Morse RP, Lacaze M, Provenzale JM, Coleman RE, et al. Human herpesvirus 6 limbic encephalitis after stem cell transplantation. Ann Neurol. 2001;50:612-9.

(5.) Caserta MT, Hall CB, Schnabel K, McIntyre K, Long C, Costanzo M, et al. Neuroinvasion and persistence of human herpesvirus 6 in children. J Infect Dis. 1994;170:1586-9.

(6.) Cermelli C, Berti R, Soldan SS, Mayne M, D'ambrosia JM, Ludwin SK, et al. High frequency of human herpesvirus 6 DNA in multiple sclerosis plaques isolated by laser microdissection. J Infect Dis. 2003;187:1377-87.

(7.) Schwartz S, Mohr A, Knauth M, Wildemann B, Storch-Hagenloeher B. Acute disseminated encephalomyelitis. A follow up study of 40 adult patients. Neurology. 2001;56:1313-8.

(8.) Hudnall SD, Rady PL, Tyring SK, Fish JC. Hydrocortisone activation of human herpesvirus 8 viral DNA replication and gene expression in vitro. Transplantation. 1999;67:648-52.

(9.) Black JB, Sanderlin KC, Goldsmith CS, Gary HE, Lopez C, Pellett PE. Growth properties of human herpesvirus-6 strain Z29.J Virol Methods. 1989;26:133-45.

Address for correspondence: Eric Denes, Service de maladies infectieuses, Centre Hospitalier Universitaire Dupuytren, 2 Ave Martin Luther King, 87042 Limoges Cedex, France; fax: [phone]; email: [e-mail]