BRIEF REPORT

A Case of Ramsay HuntLike Syndrome Caused by Herpes Simplex Virus Type 2

George A. Diaz,1 Robert M. Rakita,4 and David M. Koelle1,2,3 Departments of 1Medicine, 2Pathobiology, and 3Laboratory Medicine, University of Washington, and 4Section of Infectious Diseases, Virginia Mason Medical Center, Seattle, Washington

We report an immunocompetent patient with recurrent auricular and facial vesicles associated with painful paresthesias and facial paralysis, consistent with Ramsay Hunt syndrome [1], due to herpes simplex virus (HSV) type 2. Clinical and laboratory-proven acyclovir resistance developed during therapy. Immunologic assays revealed normal reactivity to HSV-2. In 1907, James Ramsay Hunt described a syndrome of lower motor neuron facial paralysis, otalgia, and auricular vesicles (herpes zoster oticus), which he hypothesized was due to infection of the geniculate ganglion. Other signs and symptoms include tinnitus, hyperacusis, hearing loss, vomiting, lacrimation, vertigo, loss of taste on the anterior tongue, and nystagmus, depending on the location of infection and inammation [2]. Due to the fact that cranial nerves V, VIII, IX, and X are commonly affected in addition to nerve VII, Ramsay Hunt syndrome may be described as herpes zoster cephalicus [3]. Several observations lead to the conclusion that the primary etiologic agent of Ramsay Hunt syndrome is varicella zoster virus [2]. Bell palsy (idiopathic facial paralysis), in contrast, has been attributed to herpes simplex virus (HSV) type 1. The most convincing data is from a study that used facial nerve decompression to treat medically refractory facial palsy [4]. Specimens, including an endoneural uid sample from nerve VII and a tissue sample of the posterior auricular muscle, were tested by PCR. HSV-1 DNA was found in 11 of 14 patients with Bell palsy, and varicella zoster virus DNA was found in 8 of 9 patients with Ramsay Hunt syndrome [4].
Received 21 October 2004; accepted 20 January 2005; electronically published 13 April 2005. Reprints or correspondence: Dr. George A. Diaz, 325 9th Ave., Harborview Medical Center, Box 359690, Seattle, WA 98104-2499 (geodiaz@u.washington.edu). Clinical Infectious Diseases 2005; 40:15457 2005 by the Infectious Diseases Society of America. All rights reserved. 1058-4838/2005/4010-0026$15.00

HSV-1 causes a variety of recurrent skin infections of the head, including herpes gladiatorum, which frequently involves the auricle [5]. HSV-1 is known to infect a wide variety of cephalic ganglia [6]. HSV-2 can cause auricular infection [7], but HSV infection has not been described to cause Ramsay Hunt syndrome. Case report. The patient we describe is a 42-year-old white woman. At age 13 years, she applied topical therapy to herpetiform lesions on her mother. Shortly thereafter, she was diagnosed with herpetic whitlow of the right thumb, which recurred for 3 years. At age 19 years, she developed vesicular lesions in her right external auditory canal, right pinna, and anterior cheek that lasted for 2 weeks and recurred annually with concomitant right facial paresthesias. Dental procedures on the right side of her mouth triggered these recurrent episodes. Rare left-side lesions occurred. Occasionally, she developed right shoulder and arm pain. There were no genital lesions. In 2001, when she was 39 years old, the patient had 6 episodes. MRI revealed enhancement of the right seventh cranial nerve. Results of serologic testing for HIV-1 were negative. A diagnosis of Ramsay Hunt syndrome was made, and the patient was treated episodically with valacyclovir or acyclovir at standard treatment dosages with good clinical response. In March 2002, HSV-2 was cultured from a specimen obtained from a vesicle in her right ear, and valacyclovir suppression therapy was initiated at a dosage of 500 mg/day. The patients selfreported compliance was excellent. Breakthrough vesicles occurred 7 months later, and valacyclovir treatment at a dosage of 500 mg t.i.d. did not lead to improvement. Ten days later, the patient developed right facial droop and an inability to close the right eye, which is consistent with peripheral seventh cranial nerve palsy, concurrent with right-ear canal lesions. In October 2002, cultures of specimens of vesicles in her right ear yielded HSV-2 (typing was done by uorescent monoclonal antibody testing), with an acyclovir MIC of 12 mg/mL (by dye uptake assay; susceptibility was dened as !2.0 mg/mL; Focus Technologies). The foscarnet MIC was 100 mg/mL (i.e., the isolate was susceptible). The vesicles and facial palsy resolved after 5 days of treatment with foscarnet, with resultant postherpetic neuralgia. She continued to have outbreaks in 2003, and in November, culture of a vesicular uid sample yielded HSV-2 (typing was done by uorescent monoclonal antibody testing) with an acyclovir MIC50 of 0.37 mg/mL (by plaque reduction assay; susceptibility was dened as !2.0 mg/mL; Viromed, Minnetonka).
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She was treated with valacyclovir at a dosage of 1 g three times daily, which resulted in resolution of her symptoms. The patient has continued to receive prophylaxis at a dosage of 1 g of valacyclovir twice daily, but additional outbreaks have occurred. Immunologic testing. Peripheral blood CD3, CD4, CD8, CD16, and CD56 cell percentages and cell counts were within reference ranges in March 2003 (Oregon Medical Labs). Levels of serum immunoglobulin obtained in March 2003 (Associated Regional & University Pathologists; Salt Lake City, UT) were normal except for a slightly low total IgG concentration (549 mg/dL; normal range, 6501600 mg/dL). Testing in April 2004 (Quest) again revealed a slightly low total IgG level of 681 mg/ dL (normal, 1694 mg/dL) and a low IgG3 level of 8 mg/dL (normal range, 15135 mg/dL). Type-specic immunoblotting [8] showed a normal, complex-band pattern of reactivity to HSV-2. Written, informed consent and blood samples were obtained from the patient in April 2003. PBMC were exposed to UV-irradiated HSV-2, phytohemagglutinin, and negative controls in triplicate. Proliferation was measured with tritiated thymidine [9]. Responses to HSV-2 (d counts per minute, 157,293) and PHA (d CPM, 45,000) were brisk. To study CD4 T cell functionality, IFN-g was measured by intracellular cytokine cytometry, as has been described elsewhere [9]. This revealed that 1.12% of CD4+ lymphocytes accumulated IFN-g in response to UV-irradiated HSV-2, compared with 0.57% in response to mock antigen, a net response of 0.55%, which is within the range for HSV-infected subjects [9]. Responses to PMA/ionomycin were brisk. CD40L responses in CD4+ PBMCs to stimulation with HSV-2 were measured by surface-ow cytometry. The patient had a net 1.28% of CD4+ lymphocytes that expressed CD40L, a value similar to that in healthy HSV2infected persons [9]. Discussion. This case has 2 interesting features: the ndings of HSV-2 as the etiologic agent of Ramsay Hunt syndrome, and medically signicant, laboratory-proven acyclovir resistance in the HSV-2 isolate infecting an otherwise clinically immunocompetent person. HSV and varicella zoster virus can infect diverse cephalic ganglia. Over the last few years, it has become evident that Bell palsy is likely caused by HSV-1, and that Ramsay Hunt syndrome is likely caused by varicella zoster virus. However, there is clearly an overlap in the spectrums of disease that these viruses produce. Our patient appears to have Ramsay Hunt syndrome due to HSV-2. We hypothesize that she had whitlow as a child, and, perhaps due to autoinoculation, developed recurring auricular herpes. Likely because of the interconnection of the nerves supplying the external auditory canal and the facial nerve, local spread resulted in the late development of facial nerve palsy. The results of the IgG testing raise the possibility of common variable immunodeciency, but neither the clinical features nor the laboratory results were consistent with this disorder [10].
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Limited tests of memory CD4 cell responses did not reveal an immune decit to account for the patients clinical course. Some reports indicate that Th1-like CD4 cell responses may be associated with mild HSV infection [11]. Decits in innate immunity have been reported in cases of severe HSV infection, and cross-sectional and longitudinal data have suggested an important role for CD8 T cell responses [11]. These parameters remain to be explored. The prevalence of acyclovir resistance among HSV isolates from immunocompetent patients is estimated to be 0.3%. This may be transient and clinically unimportant. Two cases of acyclovir-resistant HSV-2 causing clinically signicant recurrent disease have been described in immunocompetent patients [12, 13]. Testing was not performed prior to therapy, and it is possible that acyclovir-resistant strains were acquired during primary infection. In the case of our patient, good clinical responses were observed with acyclovir therapy early in the clinical course, suggesting primary infection with drug-susceptible virus. Serum levels of acyclovir, which are useful for documenting clinical resistance, were not obtained for our patient. In the published cases, typical resistance mutations were documented after clinical treatment failure occurred. In one study of acyclovir resistance that used a plaque reduction assay, 91% of lesions that failed to heal with acyclovir therapy were associated with in vitro acyclovir-resistant HSV infection [14]. In the case of our patient, given that treatment with clinical acyclovir failed and that the laboratory result was well above the cut-off value, we are fairly certain that the patient was infected with a resistant virus, at least during 1 recurrence. The diagnosis of acyclovir resistance was reached in the case of our patient by dye uptake assay, which has a reported 3% false positive rate [15]. Unfortunately, the isolate was not retained to identify the mechanism of resistance. The isolate obtained at follow-up was reported to be susceptible by the goldstandard plaque reduction method [15]. Recurrent infection in persons in whom resistant strains develop is generally caused by infection with wild-type drug-susceptible virus that represents latency from the primary infection [13]. Despite the limitations of assays for viral resistance, we conclude that this patient was initially infected with drug-susceptible virus, and acyclovir therapy selected for resistant virus, and recurring infection is now caused by drug-susceptible virus. Viral culture and resistance testing remain the cornerstone for diagnosis and the guide for therapy in cases where normal dosing regimens do not control outbreaks.

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Acknowledgments
Potential conicts of interest. R.R. has received speaker support from Aventix, GlaxoSmithKline, and Pzer, and D.K. has received sponsorship for his research from Antigenics and GlaxoSmithKline. G.A.D.: no conicts.

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