Methylprednisolone, Valacyclovir, or Both for Vestibular Neuritis
http://www.100md.com
《新英格兰医药杂志》
To the Editor: With respect to the report by Strupp et al. (July 22 issue),1 we wonder about the possible effect of the exclusion of 20 percent of the participants because of the lack of primary efficacy data. In addition, the rationale for the reported regimen of methylprednisolone is unclear. Why would a course of 22 days be any better than a 1-week course, which would be much simpler and encourage better compliance? Finally, we question the appropriateness of using vestibular paresis, a surrogate outcome, as a primary efficacy measure, since results from previous studies suggest that improvement in vestibular paresis might not directly correlate with patients' symptoms.2
Amit Sood, M.D.
Jon O. Ebbert, M.D.
Mayo Clinic College of Medicine
Rochester, MN 55905
References
Strupp M, Zingler VC, Arbusow V, et al. Methylprednisolone, valacyclovir, or the combination for vestibular neuritis. N Engl J Med 2004;351:354-361.
Ohbayashi S, Oda M, Yamamoto M, et al. Recovery of the vestibular function after vestibular neuronitis. Acta Otolaryngol Suppl 1993;503:31-34.
To the Editor: I was initially thrilled to read that peripheral vestibular function in patients with vestibular neuritis improves with methylprednisolone therapy, only to be disappointed that this finding might not be clinically relevant, since data were not collected on symptoms. Patients returned for electronystagmography a year after vestibular neuritis had been diagnosed, and although they were undoubtedly asked how they were doing, their answers are not reported. The authors state that they admitted all patients to the hospital and discharged them when patients were able to walk in the dark without aid. Could they provide readers with a report on the length of the hospital stay in each of the groups? This might provide some indication of the extent of early recovery in each group.
Patrick Vroomen, M.D., Ph.D.
Groningen University Hospital
9731 KL Groningen, the Netherlands
c.a.j.vroomen@neuro.azg.nl
To the Editor: Strupp et al. discuss the issue of latent herpes simplex virus type 1 (HSV-1) in cranial-nerve ganglia. Clarification of the definition of HSV latency seems warranted. Most investigators consider latent HSV-1 infection to be present when viral latency-associated transcript is present.1,2,3 The presence of HSV-1 DNA alone in vestibular ganglia or in endoneurial fluid would not indicate latency. One might consider three types of subclinical HSV infections, each of which represents a different biologic relationship between HSV-1 and host cells: persistent infection, in which viral antigen and cell-free infectious virus are present (albeit at low levels); latent infection, in which latency-associated transcript is present, but viral antigen and cell-free infectious virus are absent; and inapparent infection, in which viral DNA is present, but viral antigen is absent. Although the three operational definitions are dependent on quantitation, they represent differences in the viral state, and the differences are of biologic and medical importance.
Richard B. Tenser, M.D.
Penn State University College of Medicine
Hershey, PA 17033
rtenser@psu.edu
References
Thomas DL, Lock M, Zabolotny JM, Mohan BR, Fraser NW. The 2-kilobase intron of the herpes simplex virus type 1 latency-associated transcript has a half-life of approximately 24 hours in SY5Y and COS-1 cells. J Virol 2002;76:532-540.
Feldman LT, Ellison AR, Voytek CC, Yang L, Krause P, Margolis TP. Spontaneous molecular reactivation of herpes simplex virus type 1 latency in mice. Proc Natl Acad Sci U S A 2002;99:978-983.
Kramer MF, Cook WJ, Roth FP, et al. Latent herpes simplex virus infection of sensory neurons alters neuronal gene expression. J Virol 2003;77:9533-9541.
The authors reply: In response to the first issue raised by Drs. Sood and Ebbert: the baseline characteristics of the patients who were not included in the final analysis did not differ from the characteristics of those who were included, and there were no differences among the four groups in the numbers and characteristics of the patients excluded; therefore, it is unlikely that any such differences caused a bias. With regard to the second issue, it is conceivable that a shorter course of treatment than the one we used would also be effective and that higher doses might be even more effective. Thus, a prospective, randomized trial comparing the treatment regimen used in our study with a shorter (e.g., six-day) regimen, perhaps beginning with a higher daily dose of methylprednisolone, would make sense.
A third issue, also noted by Dr. Vroomen, relates to the clinical relevance of the outcome measures we used. Our intention was to use a validated outcome measure of efficacy that could be quantified (i.e., Jongkees's vestibular paresis formula) to compare the function of the two labyrinths. Several studies have shown that the better the recovery of peripheral vestibular function, the smaller the persistent dynamic deficit of the vestibulo-ocular reflex1 — that is, there is less oscillopsia and imbalance during head and body movements and it is less likely that symptoms of chronic vestibular deficit will develop.2 The study by Ohbayashi et al.,3 cited by Drs. Sood and Ebbert, on the correlation between recovery of peripheral vestibular function and "dizziness," was not prospective, double-blind, or placebo-controlled, and the authors did not explain how dizziness was evaluated. Their follow-up time varied between one week and nine years. Therefore, these data must be interpreted with caution.
Dr. Vroomen is correct in stating that we did not collect data on patients' symptoms. We had two reasons for not doing so, as mentioned in our article. First, experiments in animals show that corticosteroids improve central vestibular compensation. Therefore, assessment of symptoms other than vestibular paresis, such as postural imbalance, vertigo and dizziness, or the length of the hospital stay, would not differentiate between the effects of corticosteroids on the recovery of peripheral vestibular function and their effects on central vestibular compensation. In addition, there are no validated scales for measuring vertigo and dizziness.
Finally, Dr. Tenser's call for clarification of the concept of latency in HSV-1 is justified. Recent findings showed immediate-early, early, and late HSV-1 transcripts expressed in the trigeminal ganglion of latently infected mice.4 Moreover, spontaneous molecular reactivation probably elicits an antiviral immune response.5 The differences in the latent state of HSV-1 might also have an effect on pathological findings and on patients' symptoms.
Michael Strupp, M.D.
Diethilde Theil, D.V.M.
Thomas Brandt, M.D.
University of Munich
81377 Munich, Germany
mstrupp@nefo.med.uni-muenchen.de
References
Aw ST, Halmagyi GM, Curthoys IS, Todd MJ, Yavor RA. Unilateral vestibular deafferentation causes permanent impairment of the human vertical vestibulo-ocular reflex in the pitch plane. Exp Brain Res 1994;102:121-130.
Halmagyi GM. Vestibular insufficiency following unilateral vestibular deafferentation. Aust J Otolaryngol 1994;1:510-2.
Ohbayashi S, Oda M, Yamamoto M, et al. Recovery of the vestibular function after vestibular neuronitis. Acta Otolaryngol Suppl 1993;503:31-34.
Feldman LT, Ellison AR, Voytek CC, Yang L, Krause P, Margolis TP. Spontaneous molecular reactivation of herpes simplex virus type 1 latency in mice. Proc Natl Acad Sci U S A 2002;99:978-983.
Theil D, Derfuss T, Paripovic I, et al. Latent herpesvirus infection in human trigeminal ganglia causes chronic immune response. Am J Pathol 2003;163:2179-2184.
Amit Sood, M.D.
Jon O. Ebbert, M.D.
Mayo Clinic College of Medicine
Rochester, MN 55905
References
Strupp M, Zingler VC, Arbusow V, et al. Methylprednisolone, valacyclovir, or the combination for vestibular neuritis. N Engl J Med 2004;351:354-361.
Ohbayashi S, Oda M, Yamamoto M, et al. Recovery of the vestibular function after vestibular neuronitis. Acta Otolaryngol Suppl 1993;503:31-34.
To the Editor: I was initially thrilled to read that peripheral vestibular function in patients with vestibular neuritis improves with methylprednisolone therapy, only to be disappointed that this finding might not be clinically relevant, since data were not collected on symptoms. Patients returned for electronystagmography a year after vestibular neuritis had been diagnosed, and although they were undoubtedly asked how they were doing, their answers are not reported. The authors state that they admitted all patients to the hospital and discharged them when patients were able to walk in the dark without aid. Could they provide readers with a report on the length of the hospital stay in each of the groups? This might provide some indication of the extent of early recovery in each group.
Patrick Vroomen, M.D., Ph.D.
Groningen University Hospital
9731 KL Groningen, the Netherlands
c.a.j.vroomen@neuro.azg.nl
To the Editor: Strupp et al. discuss the issue of latent herpes simplex virus type 1 (HSV-1) in cranial-nerve ganglia. Clarification of the definition of HSV latency seems warranted. Most investigators consider latent HSV-1 infection to be present when viral latency-associated transcript is present.1,2,3 The presence of HSV-1 DNA alone in vestibular ganglia or in endoneurial fluid would not indicate latency. One might consider three types of subclinical HSV infections, each of which represents a different biologic relationship between HSV-1 and host cells: persistent infection, in which viral antigen and cell-free infectious virus are present (albeit at low levels); latent infection, in which latency-associated transcript is present, but viral antigen and cell-free infectious virus are absent; and inapparent infection, in which viral DNA is present, but viral antigen is absent. Although the three operational definitions are dependent on quantitation, they represent differences in the viral state, and the differences are of biologic and medical importance.
Richard B. Tenser, M.D.
Penn State University College of Medicine
Hershey, PA 17033
rtenser@psu.edu
References
Thomas DL, Lock M, Zabolotny JM, Mohan BR, Fraser NW. The 2-kilobase intron of the herpes simplex virus type 1 latency-associated transcript has a half-life of approximately 24 hours in SY5Y and COS-1 cells. J Virol 2002;76:532-540.
Feldman LT, Ellison AR, Voytek CC, Yang L, Krause P, Margolis TP. Spontaneous molecular reactivation of herpes simplex virus type 1 latency in mice. Proc Natl Acad Sci U S A 2002;99:978-983.
Kramer MF, Cook WJ, Roth FP, et al. Latent herpes simplex virus infection of sensory neurons alters neuronal gene expression. J Virol 2003;77:9533-9541.
The authors reply: In response to the first issue raised by Drs. Sood and Ebbert: the baseline characteristics of the patients who were not included in the final analysis did not differ from the characteristics of those who were included, and there were no differences among the four groups in the numbers and characteristics of the patients excluded; therefore, it is unlikely that any such differences caused a bias. With regard to the second issue, it is conceivable that a shorter course of treatment than the one we used would also be effective and that higher doses might be even more effective. Thus, a prospective, randomized trial comparing the treatment regimen used in our study with a shorter (e.g., six-day) regimen, perhaps beginning with a higher daily dose of methylprednisolone, would make sense.
A third issue, also noted by Dr. Vroomen, relates to the clinical relevance of the outcome measures we used. Our intention was to use a validated outcome measure of efficacy that could be quantified (i.e., Jongkees's vestibular paresis formula) to compare the function of the two labyrinths. Several studies have shown that the better the recovery of peripheral vestibular function, the smaller the persistent dynamic deficit of the vestibulo-ocular reflex1 — that is, there is less oscillopsia and imbalance during head and body movements and it is less likely that symptoms of chronic vestibular deficit will develop.2 The study by Ohbayashi et al.,3 cited by Drs. Sood and Ebbert, on the correlation between recovery of peripheral vestibular function and "dizziness," was not prospective, double-blind, or placebo-controlled, and the authors did not explain how dizziness was evaluated. Their follow-up time varied between one week and nine years. Therefore, these data must be interpreted with caution.
Dr. Vroomen is correct in stating that we did not collect data on patients' symptoms. We had two reasons for not doing so, as mentioned in our article. First, experiments in animals show that corticosteroids improve central vestibular compensation. Therefore, assessment of symptoms other than vestibular paresis, such as postural imbalance, vertigo and dizziness, or the length of the hospital stay, would not differentiate between the effects of corticosteroids on the recovery of peripheral vestibular function and their effects on central vestibular compensation. In addition, there are no validated scales for measuring vertigo and dizziness.
Finally, Dr. Tenser's call for clarification of the concept of latency in HSV-1 is justified. Recent findings showed immediate-early, early, and late HSV-1 transcripts expressed in the trigeminal ganglion of latently infected mice.4 Moreover, spontaneous molecular reactivation probably elicits an antiviral immune response.5 The differences in the latent state of HSV-1 might also have an effect on pathological findings and on patients' symptoms.
Michael Strupp, M.D.
Diethilde Theil, D.V.M.
Thomas Brandt, M.D.
University of Munich
81377 Munich, Germany
mstrupp@nefo.med.uni-muenchen.de
References
Aw ST, Halmagyi GM, Curthoys IS, Todd MJ, Yavor RA. Unilateral vestibular deafferentation causes permanent impairment of the human vertical vestibulo-ocular reflex in the pitch plane. Exp Brain Res 1994;102:121-130.
Halmagyi GM. Vestibular insufficiency following unilateral vestibular deafferentation. Aust J Otolaryngol 1994;1:510-2.
Ohbayashi S, Oda M, Yamamoto M, et al. Recovery of the vestibular function after vestibular neuronitis. Acta Otolaryngol Suppl 1993;503:31-34.
Feldman LT, Ellison AR, Voytek CC, Yang L, Krause P, Margolis TP. Spontaneous molecular reactivation of herpes simplex virus type 1 latency in mice. Proc Natl Acad Sci U S A 2002;99:978-983.
Theil D, Derfuss T, Paripovic I, et al. Latent herpesvirus infection in human trigeminal ganglia causes chronic immune response. Am J Pathol 2003;163:2179-2184.