Abstract
Objectives
The aims of this study were to verify the characteristics of zoster sine herpete (ZSH) causing facial palsy and the effects of different treatments and to confirm the difference from other etiologies.
Methods
From March 2010 to March 2011, a prospective study was performed on patients with ZSH with facial palsy. Patients were divided into a steroid-treated group and a steroid-antiviral combination group, and then the effects according to regimen of treatment were prospectively analyzed. Last, the difference between the ZSH group and patients diagnosed with Bell palsy and Ramsay Hunt syndrome in the same study period was confirmed retrospectively.
Results
Forty-five patients were diagnosed as having ZSH. Significant improvement was not observed in the ZSH group regardless of the treatment regimen during a 3-week period ( P < .05). In patients with ZSH with accompanying typical pain, significant continuous improvement after 6 weeks was observed in patients with combination therapy ( P < .05). Compared with patients with Bell palsy and Ramsay Hunt syndrome, there was a significant difference in recovery rate between patients with ZSH (accompanying pain) and those with Bell palsy (89.9%) ( P < .05).
Conclusion
The initiation of recovery in ZSH started later than that in other peripheral palsies, and slower recovery was shown in patients with ZSH with pain compared with those with Bell palsy. Steroid-antiviral combination therapy was a more effective regimen for treatment compared with steroid-only treatment. To improve the accuracy of ZSH diagnosis, confirming the presence of accompanying typical pain is necessary.
1
Introduction
The annual incidence of Bell palsy as the most common etiology of acute peripheral facial palsy is observed in 15 to 30 people per 100 000. In the past, the cause of Bell palsy was considered idiopathic . Recently, reactivation of herpes simplex virus (HSV) type 1 was presumed as one of the most common causes of Bell palsy . In addition, varicella zoster virus (VZV) can also cause facial palsy. Ramsay Hunt syndrome (RHS), when accompanied by vesicular eruption around the affected ear or in the oropharynx with facial palsy, is caused by VZV.
However, facial palsies caused by VZV are not always accompanied by vesicular eruption, and these cases are referred to as zoster sine herpete (ZSH). Distinguishing ZSH from Bell palsy is difficult, and ZSH is often clinically diagnosed as Bell palsy.
According to previous studies, 100% of the remedial value was reported in 13 patients who were prescribed acyclovir-prednisone treatment within 3 days of diagnosis . In general, facial palsy caused by reactivation of VZV is presumed to show poorer prognosis compared with reactivation of HSV . A multicenter study reported that there were no statistically significant changes in recovery according to the presence of activation of VZV .
In the present study, based on the review of ZSH literature and analysis of our patients’ data, the authors discuss and report the ZSH characteristics causing facial palsy, the difference in results caused by treatment regimens, and the difference between ZSH and other peripheral palsies. In particular, when evaluating the presence of accompanying pain, differences in the pain characteristics were confirmed.
2
Materials and methods
2.1
Patients
From March 2010 to March 2011, a prospective study was performed on patients who visited our tertiary medical center because of acute unilateral peripheral facial paralysis that occurred within 7 days of diagnosis. Precise history taking, thorough physical examination, and enzyme-linked immune sorbent assay (ELISA) were performed on the first day. All patients were hospitalized for a week. Age, sex, laterality, duration from the onset to treatment, history of facial palsy and associated symptoms such as pain around the ear, taste disturbance, and hyperacusis were documented. In the ELISA, after collecting the patient’s vein blood on the first day, the titer was measured using ELISA kits (Platelia VZV immunoglobulin [Ig] M, IgG, HSV (1 + 2) IgM, IgG; Bio-Rad, Hercules, CA). If the titer measured more than 1.2 times greater than the baseline, it was defined as positive. In addition, if the titer increased more than 4 times over the baseline, it was considered as reactivation or recent infection. Zoster sine herpete was defined if there was no sign of vesicular eruption around the affected ear before and after facial palsy and if VZV IgM was found or the VZV IgG titer increased more than 4 times. The present study included all patients diagnosed as having ZSH. Patients who had accompanying pain around the affected ear at the time of diagnosis were documented as “typical” ZSH. For healthy controls, enzyme immunoassay was performed in 48 healthy people (age, 44.9 ± 18.6 years; male-to-female ratio, 20:28) who visited the hospital for a health examination and had no facial palsy or history of recent infection.
2.2
Treatment protocol
Patients with ZSH were divided into 2 groups by simple randomization using a computer. For treatment, one group was treated with steroid and the other group with steroid-antiviral combination therapy. The drug therapy protocol consisted of patients assigned to the same group being treated on the same schedule. For the steroid treatment, methylprednisone was used for 10 days (64 mg/d over 4 days and then tapering to 48 mg/d for 2 days, 32 mg/d for 2 days, and 16 mg/d for 2 days). For antiviral therapy, oral valacyclovir was administered at 3000 mg/d for 7 days. Steroid and valacyclovir were administered simultaneously to patients who were assigned to be treated with combination therapy.
2.3
Follow-up period
After leaving the hospital, all patients underwent outpatient observation at 3 and 6 weeks and at 3 and 6 months. For evaluating facial palsy, Facial Nerve Grading System 2.0 was used . Grades 1 and 2 at 6 months from onset were defined as complete recovery, and grade 3 or more was defined as incomplete recovery.
2.4
Objectives
Based on the obtained data, the difference in the ELISA results between the ZSH group and the healthy controls was confirmed. Next, the differences in recovery according to the treatment regimen were analyzed prospectively. Last, the prognosis between patients with ZSH and patients diagnosed as having Bell palsy or RHS during the same period were retrospectively compared ( Fig. 1 ).
2.5
Bell palsy and RHS
The diagnosis of Bell palsy was made when the following conditions were satisfied: (1) unilateral facial palsy within 7 days of diagnosis, (2) no sign of vesicular eruption around the ear or pharyngolaryngeal mucosa before or after hospitalization, and (3) no specific finding observed on ELISA. The RHS group was defined if vesicular eruption occurred.
Steroid treatment was administered to treat patients with Bell palsy, and steroid-antiviral combination therapy was given to the RSH group. If vesicular eruption occurred during hospitalization but had not occurred on the date of admission, valacyclovir was additionally administered, and the patient was categorized into the RHS group. Eventually, 1 patient was relocated to the RHS group on the sixth day of hospitalization.
2.6
Exclusion criteria
The criteria for exclusion were as follows: (1) facial palsy that occurred more than 7 days prior; (2) suspected case of meningitis, myelitis, or vasculopathy; (3) patients who underwent VZV vaccination for adults; (4) patients who could not be observed for at least 6 months; (5) patients who refused to participate in the present study; (6) several different types of treatments originally used for treatment; (7) age less than 15 years; (8) pregnant or breast-feeding; (9) uncontrolled diabetes or hypertension; (10) suspicion of Borrelia infection; and (11) patients with a tendency for neuropsychiatric disease.
2.7
Statistical analysis
Wilcoxon signed rank test were performed to evaluate changes in facial nerve function over time. Student t test and Mann-Whitney U test were performed to compare the averages of the 2 groups. Fisher exact test was used to conduct statistical analysis of nominal variables. SPSS version 18.0 (SPSS Inc, Chicago, IL) was used for statistical analysis, with the significance level set at P < .05.
2
Materials and methods
2.1
Patients
From March 2010 to March 2011, a prospective study was performed on patients who visited our tertiary medical center because of acute unilateral peripheral facial paralysis that occurred within 7 days of diagnosis. Precise history taking, thorough physical examination, and enzyme-linked immune sorbent assay (ELISA) were performed on the first day. All patients were hospitalized for a week. Age, sex, laterality, duration from the onset to treatment, history of facial palsy and associated symptoms such as pain around the ear, taste disturbance, and hyperacusis were documented. In the ELISA, after collecting the patient’s vein blood on the first day, the titer was measured using ELISA kits (Platelia VZV immunoglobulin [Ig] M, IgG, HSV (1 + 2) IgM, IgG; Bio-Rad, Hercules, CA). If the titer measured more than 1.2 times greater than the baseline, it was defined as positive. In addition, if the titer increased more than 4 times over the baseline, it was considered as reactivation or recent infection. Zoster sine herpete was defined if there was no sign of vesicular eruption around the affected ear before and after facial palsy and if VZV IgM was found or the VZV IgG titer increased more than 4 times. The present study included all patients diagnosed as having ZSH. Patients who had accompanying pain around the affected ear at the time of diagnosis were documented as “typical” ZSH. For healthy controls, enzyme immunoassay was performed in 48 healthy people (age, 44.9 ± 18.6 years; male-to-female ratio, 20:28) who visited the hospital for a health examination and had no facial palsy or history of recent infection.
2.2
Treatment protocol
Patients with ZSH were divided into 2 groups by simple randomization using a computer. For treatment, one group was treated with steroid and the other group with steroid-antiviral combination therapy. The drug therapy protocol consisted of patients assigned to the same group being treated on the same schedule. For the steroid treatment, methylprednisone was used for 10 days (64 mg/d over 4 days and then tapering to 48 mg/d for 2 days, 32 mg/d for 2 days, and 16 mg/d for 2 days). For antiviral therapy, oral valacyclovir was administered at 3000 mg/d for 7 days. Steroid and valacyclovir were administered simultaneously to patients who were assigned to be treated with combination therapy.
2.3
Follow-up period
After leaving the hospital, all patients underwent outpatient observation at 3 and 6 weeks and at 3 and 6 months. For evaluating facial palsy, Facial Nerve Grading System 2.0 was used . Grades 1 and 2 at 6 months from onset were defined as complete recovery, and grade 3 or more was defined as incomplete recovery.
2.4
Objectives
Based on the obtained data, the difference in the ELISA results between the ZSH group and the healthy controls was confirmed. Next, the differences in recovery according to the treatment regimen were analyzed prospectively. Last, the prognosis between patients with ZSH and patients diagnosed as having Bell palsy or RHS during the same period were retrospectively compared ( Fig. 1 ).
2.5
Bell palsy and RHS
The diagnosis of Bell palsy was made when the following conditions were satisfied: (1) unilateral facial palsy within 7 days of diagnosis, (2) no sign of vesicular eruption around the ear or pharyngolaryngeal mucosa before or after hospitalization, and (3) no specific finding observed on ELISA. The RHS group was defined if vesicular eruption occurred.
Steroid treatment was administered to treat patients with Bell palsy, and steroid-antiviral combination therapy was given to the RSH group. If vesicular eruption occurred during hospitalization but had not occurred on the date of admission, valacyclovir was additionally administered, and the patient was categorized into the RHS group. Eventually, 1 patient was relocated to the RHS group on the sixth day of hospitalization.
2.6
Exclusion criteria
The criteria for exclusion were as follows: (1) facial palsy that occurred more than 7 days prior; (2) suspected case of meningitis, myelitis, or vasculopathy; (3) patients who underwent VZV vaccination for adults; (4) patients who could not be observed for at least 6 months; (5) patients who refused to participate in the present study; (6) several different types of treatments originally used for treatment; (7) age less than 15 years; (8) pregnant or breast-feeding; (9) uncontrolled diabetes or hypertension; (10) suspicion of Borrelia infection; and (11) patients with a tendency for neuropsychiatric disease.
2.7
Statistical analysis
Wilcoxon signed rank test were performed to evaluate changes in facial nerve function over time. Student t test and Mann-Whitney U test were performed to compare the averages of the 2 groups. Fisher exact test was used to conduct statistical analysis of nominal variables. SPSS version 18.0 (SPSS Inc, Chicago, IL) was used for statistical analysis, with the significance level set at P < .05.
3
Results
Forty-five patients with facial paralysis met the inclusion criteria and were diagnosed as having ZSH by recent infection or reactivation of VZV. Among the patients with ZSH, 46.7% (n = 21) experienced pain around the ear and were classified as typical ZSH.
3.1
Demographics of patients with ZSH
The characteristics of the patients diagnosed as having ZSH were as follows: 46.7% (n = 21) were male and 53.3% (n = 24) were female. For laterality, 46.7% (n = 21) experienced right-sided facial palsy and 53.3% (n = 24) experienced left-sided facial palsy. The average (SD) age was 48 (15.2) years (range, 15–81 years). The time from onset to hospitalization was 2.3 (1.6) days (range, 0–6 days). Regarding associated diseases, well-controlled diabetes and hypertension were observed in 22.2% (n = 10) and 28.9% (n = 13) of patients, respectively; 46.7% (n = 21) of patients experienced pain around the ear and were classified as typical ZSH. For other associated symptoms, taste disturbance and hyperacusis were observed in 22.2% (n = 10) and 6.7% (n = 3) of patients, respectively; 15.6% (n = 7) of patients had a history of facial palsy. According to facial nerve grade at the initial visit, the patients were graded as 5 (6.7% [n = 3]), grade 4 (44.4% [n = 20]), and grade 3 (48.9% [n = 22]).
3.2
Comparison of ELISA results in the ZSH group vs control group
All patients in the ZSH group were anti–VZV IgG positive with a titer greater than 4 times the baseline, and 15.6% (n = 7) of patients were anti–VZV IgM Ab positive. For HSV, 2.2% (n = 1) of patients were anti–HSV IgM positive, and anti–HSV IgG positivity was detected in 95.6% (n = 43) of the patients. The titer of anti–HSV IgG was increased more than 4 times in 55.6% (n = 25) of the patients.
In typical ZSH (with pain), anti–VZV IgM positivity was detected in 19.0% (n = 4), and no patients showed anti–HSV IgM. Anti–HSV IgG positivity was detected in 95.2% (n = 20) of the patients. The titer of anti–HSV IgG was increased more than 4 times relative to the baseline in 47.6% (n = 10) of the patients.
In the healthy controls, anti–HSV IgM and anti–VZV IgM were not detected in any patient. The results from other titers were as follows: anti–HSV IgG positive, 87.5% (n = 42), and anti–VZV IgG, 91.7% (n = 44). Increased titers of more than 4 times the baseline of anti–HSV IgG and anti–VZV IgG were found in 27.1% (n = 13) and 10.4% (n = 5) of the patients, respectively.
In samples where anti–VZV IgG and anti–HSV IgG titers were increased more than 4 times and VZV IgM was detected, there was a significant difference between the ZSH group and the healthy controls ( P < .05). However, there was no significant difference in the detection of anti–VZV IgG, anti–HSV IgM, and IgG ( P > .05, Fisher exact test) ( Fig. 2 ).
