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Acyclovir in the treatment of Ramsay Hunt syndrome
Acyclovir in the treatment of Ramsay Hunt syndrome NECHAMA URI,
MD,
ELHANAN GREENBERG,
MD,
RUTH KITZES-COHEN,
Ramsay Hunt syndrome is an herpetic disease with ominous prognosis regarding the facial nerve. Treatment with acyclovir, a well-known virostatic agent, has been given in a small number of patients in recent years with excellent results. We report on the administration of acyclovir intravenously for 7 days in 31 patients with Ramsay Hunt syndrome, with overall recovery rate of 82.6%. There were no side effects regarding this treatment. (Otolaryngol Head Neck Surg 2003;129:379-81.)
I n 1907, J. Ramsay Hunt described a syndrome characterized by facial paralysis, inner ear dysfunction, and periauricular pain and herpetiform vesicles of the pinna.1 Today, this syndrome is referred to as Ramsay Hunt syndrome (RHS), or herpes zoster oticus. There is evidence that the etiology of RHS is recrudescence of latent varicella zoster virus located in the affected geniculate auditory or vestibular ganglia, but many authors have questioned the validity of this theory.2-4 Payten and Dawes3 review the pathologic studies of herpes zoster oticus with facial paralysis for a 60-year interval. They reported that the literature supported a diffuse lymphocytic infiltration along the entire course of the facial nerve rather than isolated to the geniculate ganglion. Wackym5 in 1997 suggested that latent varicella zoster virus is located in the geniculate ganglia and may be present in the auditory and vestibular primary afferent ganglia in some patients. Herpes zoster paralysis is associated with a poorer prognosis than the idiopathic facial paralysis (Bell’s palsy) for recovery of facial function even with a high dose of corticosteroids.6-8 From the Departments of Otolaryngology–Head and Neck Surgery (Drs Uri, Greenberg, and Doweck) and Clinical Pharmacology and Infectious Disease (Dr Kitzes-Cohen), Carmel Medical Center. Reprint requests: Nechama Uri, MD, Otolaryngology–Head and Neck Surgery Department, Carmel Medical Center, 7 Michal St, Haifa 34362, Israel. Copyright © 2003 by the American Academy of Otolaryngology–Head and Neck Surgery Foundation, Inc. 0194-5998/2003/$30.00 ⫹ 0 doi:10.1016/S0194-5998(02)01305-6
MD,
and ILANA DOWECK,
MD,
Haifa, Israel
May et al9 investigated 117 patients with RHS and noted only 60% had good recovery. The presence of possible viral etiology and poor facial function outcome led some investigators to use antiviral agent in this entity. The use of acyclovir was reported in some preliminary reports,10-12 with better results. This report documents experience with 31 RHS patients who were treated with acyclovir and hydrocortisone. MATERIALS AND METHODS From 1987 to 1997, 31 patients with RHS were treated in the Carmel Medical Center. All patients were in their first week of illness and were administered intravenous acyclovir 5 mg/kg every 8 hours for 7 days and hydrocortisone 100 mg 3 times per day. The acyclovir was administered with adequate hydration, and care was taken for slow flow of the medication. Every patient underwent blood tests that included renal and liver function, as well as an audiogram and chest radiograph. The facial function was assessed on admission and 1 week, 3 months, and 1 year after treatment using the House-Brackmann grading system (HBGS).13 A good recovery is regarded as I to II in the HBGS. Twenty-three patients were followed for at least 1 year and underwent statistical evaluation. The medical charts were reviewed, and statistical evaluation was made using Mann-Whitney, 2, Wilcoxon rank, and t tests. RESULTS Thirty-one patients were included in the study (12 males and 19 females; mean age, 50.8 years; age range, 6 to 77 years). The delay from onset of the disease until treatment began was 1 to 7 days, with median of 3 days. Fourteen patients also had vestibular symptoms and sensory neural hearing loss. Facial function grading at presentation according to the HBGS showed that 22 patients had 379
Otolaryngology– Head and Neck Surgery October 2003
380 URI et al
Table 1. House-Brackmann classification of facial nerve function before and after treatment with acyclovir Facial nerve function at presentation
IV No. % V No. % VI No. % Total No. %
Facial nerve function after treatment I
II
2 8.7
III
IV
V
1 4.3
Total
3 13
2 8.7
2 8.7
11 4 47.8 17.4
1 4.3
1 4.3
1 4.3
15 4 65.2 17.4
2 8.7
1 4.3
1 4.3
18 78.3 23 100
grade VI, 3 patients had grade V, and 5 patients had grade IV. The median was grade VI. Twenty-three patients were followed for at least 1 year. After treatment, 15 patients were classified as grade I, 4 patients as grade II, 2 patients as grade III, and 2 patients as classified as grades IV/V. The median grade was I. There was no significant difference in recovery rate of facial nerve function when dealing with age or gender. Using the Wilcoxon test, patients with no auditory symptoms improved better than did those with symptoms (P ⫽ 0.05), as did patients with no vestibular symptoms (P ⫽ 0.029). When comparing the patients’ facial function degree before and after treatment using t tests, the difference was statistically significant at P ⫽ 0.001. Use of the Wilcoxon rank test showed that all 23 patients had a recovery (partial or complete) of facial function after treatment with acyclovir (Z ⫽ 4.26, P ⬍ 0.001). The relationship between the facial nerve function before and after treatment is shown in Table 1. Of the patients, 82.6% recovered completely (grade I) or remained with mild dysfunction only (grade II). When dealing with the group of patients with complete paralysis at presentation (grade VI), 65.2% of them recovered to grade I/II. The patient group was divided into 2 subgroups according their arrival day. Group A includes patients with a 1- to 3-day delay, and group B
include patients with a 4- to 7-day delay. Using the Mann-Whitney test, we compared the facial function before and after treatment. No significant differences were found between the 2 groups (Table 2). No immediate or late side effects were noticed during or after treatment. DISCUSSION Herpes zoster oticus is a debilitating disease responsible for 12% of cases of facial nerve paralysis.8 The facial palsy of RHS patients has a worse prognosis than that of patients with Bell’s palsy.7 Only 10% of patients with complete facial paralysis recover completely.8 The traditional treatment of RHS with high-dose corticosteroids changed with the development of the new virostatic agents, particularly acyclovir. Acyclovir has a good virostatic action on herpes group organisms with effect through interference with DNA polymerase and through inhibition of its replication. Therefore, better results are achieved when administered early in the disease. We included in our study only patients within 7 days from onset of paralysis, and no correlation was found between recovery and the day on which treatment began. Murakami et al14 divided their 80 patients into 3 subgroups. Twenty-eight patients were treated within 3 days of onset, 29 patients were treated within 3 to 7 days, and 23 patients were treated more than 7 days after onset. They found a significant difference between these groups, in favor for the early administration. Treatment should be initiated as early as possible, because complete recovery cannot take place once nerve degeneration has occurred. The parental dosage of acyclovir is 15 mg/kg per day. Because absorption from the gastrointestinal tract is only 15% to 25% of the ingested dose, higher doses are proposed for oral therapy admission. The recommended dose is 800 mg 5 times per day. Most investigators10-12 treat their patients with intravenous acyclovir, but there are reports14 of oral acyclovir administration. Murakami et al14 treated 48 of their 80 patients with oral acyclovir and found no significant difference in facial nerve outcome between intravenous and oral acyclovir treatment groups. We treated an additional 3 patients with oral acyclovir and measured their drug
Otolaryngology– Head and Neck Surgery Volume 129 Number 4
URI et al 381
Table 2. Comparison between presentation and posttreatment condition of patients with 1- to 3-day and those with 4- to 7-day interval between onset and treatment
Patient’s condition at presentation
Patient’s condition posttreatment
Delay (days)
No. of patients
Median
1-3 4-7 Total 1-3 4-7 Total
15 15 30 12 11 23
VI VI VI I I I
blood levels, but the follow-up for these patients was too short to measure recovery. There are only a few reports in the literature dealing with acyclovir, usually in combination with corticosteroids, in the treatment of RHS. Dickens et al11 reported the results of in the treatment of 8 patients. Six patients had complete paralysis, and 4 of them recovered completely. Stafford and Welch10 had similar results. We reported previously12 that of 5 patients with complete paralysis, 4 had good recovery. Of our patients in the present study, 82.6% had a recovery rate of HBGS I/II. A total of 65% obtained complete recovery. These results are much better than those with steroid treatment alone. Murakami et al14 found that 52% of patients obtained complete recovery and 81% had good recovery (grades I and II). An interesting observation was made about the relation between the audiovestibular symptoms and recovery rates. When no such symptoms exist, there is a better prognosis. The study was not controlled and double blind because we consider that unethical; it is obvious that the early treatment with prednisone and acyclovir is the treatment of choice for herpes zoster oticus. CONCLUSION Treatment of RHS patients with intravenous hydrocortisone and acyclovir become well establish fact in the last few years. In our study this treatment was given in 31 patients with overall recovery of 82.6% with no side effects. Oral treatment should be more investigated to reduce hos-
Mann-Whitney U
P
85.5
0.262
52.0
0.413
pitalization and lower the cost effectiveness of the treatment. REFERENCES
1. Hunt JR. On herpetic inflammations of the geniculate ganglion, a new syndrome and its complication. J Nerve Ment Dis 1907;34:73-96. 2. Gulderg-Moller J, Olsen S, Kettel K. Histopathology of the facial nerve in herpes zoster oticus. Arch Otolaryngol 1959;69:266-75. 3. Payten RJ, Dawes DDK. Herpes zoster of the head and neck. J Laryngol Otol 1972;86:1031-55. 4. Aviel A, Marshak G. Ramsay Hunt syndrome: a cranial polyneuropathy. Am J Otolaryngol 1982;3:61-6. 5. Wackym PA. Molecular temporal bone pathology: II. Ramsay Hunt syndrome (herpes zoster oticus). Laryngoscope 1997;107:1165-75. 6. Kanzaki J. Electrodiagnostic findings in the early stages of Bell’s palsy and Ramsay-Hunt’s syndrome. Acta Otolaryngol (Suppl) (Stockh) 1988;446(suppl):42-6. 7. Devriese PP, Moesker WH. The natural history of facial paralysis in herpes zoster. Clin Otolaryngol 1988;13:28998. 8. Robillard ZRB, Hilsinger RL Jr, Adour KK. Ramsay Hunt facial paralysis: clinical analysis of 185 patients. Otolaryngol Head Neck Surg 1986;95:292-7. 9. May M, Podvinec M, Ulrich J, et al. Idiopathic (Bell’s) palsy, herpes zoster cephalicus and other facial nerve disorders of viral origin. In: May M, editor. The facial nerve. New York: Thieme-Stratton; 1986. p. 365-99. 10. Stafford FW, Welch AR. The use of acyclovir in Ramsay Hunt syndrome. J Laryngol Otol 1986;100:337-40. 11. Dickins JRE, Smith JT, Graham SS. Herpes zoster oticus: treatment with intravenous acyclovir. Laryngoscopi 1988;98:776-9. 12. Uri N, Greenberg E, Kitzes-Cohen R. et al. Herpes zoster oticus: treatment with acyclovir. Ann Otol Rhinol Laryngol 1992;101:161-2. 13. House JW, Brackmann DE. Facial nerve grading system. Otolaryngol Head Neck Surg 1985;93:146-7. 14. Murakami S, Hato N, Horluchi J. Treatment of Ramsay Hunt syndrome with acyclovir-prednisone: significance of early diagnosis and treatment. Ann Neurol 1997;41: 353-7.
MD,
ELHANAN GREENBERG,
MD,
RUTH KITZES-COHEN,
Ramsay Hunt syndrome is an herpetic disease with ominous prognosis regarding the facial nerve. Treatment with acyclovir, a well-known virostatic agent, has been given in a small number of patients in recent years with excellent results. We report on the administration of acyclovir intravenously for 7 days in 31 patients with Ramsay Hunt syndrome, with overall recovery rate of 82.6%. There were no side effects regarding this treatment. (Otolaryngol Head Neck Surg 2003;129:379-81.)
I n 1907, J. Ramsay Hunt described a syndrome characterized by facial paralysis, inner ear dysfunction, and periauricular pain and herpetiform vesicles of the pinna.1 Today, this syndrome is referred to as Ramsay Hunt syndrome (RHS), or herpes zoster oticus. There is evidence that the etiology of RHS is recrudescence of latent varicella zoster virus located in the affected geniculate auditory or vestibular ganglia, but many authors have questioned the validity of this theory.2-4 Payten and Dawes3 review the pathologic studies of herpes zoster oticus with facial paralysis for a 60-year interval. They reported that the literature supported a diffuse lymphocytic infiltration along the entire course of the facial nerve rather than isolated to the geniculate ganglion. Wackym5 in 1997 suggested that latent varicella zoster virus is located in the geniculate ganglia and may be present in the auditory and vestibular primary afferent ganglia in some patients. Herpes zoster paralysis is associated with a poorer prognosis than the idiopathic facial paralysis (Bell’s palsy) for recovery of facial function even with a high dose of corticosteroids.6-8 From the Departments of Otolaryngology–Head and Neck Surgery (Drs Uri, Greenberg, and Doweck) and Clinical Pharmacology and Infectious Disease (Dr Kitzes-Cohen), Carmel Medical Center. Reprint requests: Nechama Uri, MD, Otolaryngology–Head and Neck Surgery Department, Carmel Medical Center, 7 Michal St, Haifa 34362, Israel. Copyright © 2003 by the American Academy of Otolaryngology–Head and Neck Surgery Foundation, Inc. 0194-5998/2003/$30.00 ⫹ 0 doi:10.1016/S0194-5998(02)01305-6
MD,
and ILANA DOWECK,
MD,
Haifa, Israel
May et al9 investigated 117 patients with RHS and noted only 60% had good recovery. The presence of possible viral etiology and poor facial function outcome led some investigators to use antiviral agent in this entity. The use of acyclovir was reported in some preliminary reports,10-12 with better results. This report documents experience with 31 RHS patients who were treated with acyclovir and hydrocortisone. MATERIALS AND METHODS From 1987 to 1997, 31 patients with RHS were treated in the Carmel Medical Center. All patients were in their first week of illness and were administered intravenous acyclovir 5 mg/kg every 8 hours for 7 days and hydrocortisone 100 mg 3 times per day. The acyclovir was administered with adequate hydration, and care was taken for slow flow of the medication. Every patient underwent blood tests that included renal and liver function, as well as an audiogram and chest radiograph. The facial function was assessed on admission and 1 week, 3 months, and 1 year after treatment using the House-Brackmann grading system (HBGS).13 A good recovery is regarded as I to II in the HBGS. Twenty-three patients were followed for at least 1 year and underwent statistical evaluation. The medical charts were reviewed, and statistical evaluation was made using Mann-Whitney, 2, Wilcoxon rank, and t tests. RESULTS Thirty-one patients were included in the study (12 males and 19 females; mean age, 50.8 years; age range, 6 to 77 years). The delay from onset of the disease until treatment began was 1 to 7 days, with median of 3 days. Fourteen patients also had vestibular symptoms and sensory neural hearing loss. Facial function grading at presentation according to the HBGS showed that 22 patients had 379
Otolaryngology– Head and Neck Surgery October 2003
380 URI et al
Table 1. House-Brackmann classification of facial nerve function before and after treatment with acyclovir Facial nerve function at presentation
IV No. % V No. % VI No. % Total No. %
Facial nerve function after treatment I
II
2 8.7
III
IV
V
1 4.3
Total
3 13
2 8.7
2 8.7
11 4 47.8 17.4
1 4.3
1 4.3
1 4.3
15 4 65.2 17.4
2 8.7
1 4.3
1 4.3
18 78.3 23 100
grade VI, 3 patients had grade V, and 5 patients had grade IV. The median was grade VI. Twenty-three patients were followed for at least 1 year. After treatment, 15 patients were classified as grade I, 4 patients as grade II, 2 patients as grade III, and 2 patients as classified as grades IV/V. The median grade was I. There was no significant difference in recovery rate of facial nerve function when dealing with age or gender. Using the Wilcoxon test, patients with no auditory symptoms improved better than did those with symptoms (P ⫽ 0.05), as did patients with no vestibular symptoms (P ⫽ 0.029). When comparing the patients’ facial function degree before and after treatment using t tests, the difference was statistically significant at P ⫽ 0.001. Use of the Wilcoxon rank test showed that all 23 patients had a recovery (partial or complete) of facial function after treatment with acyclovir (Z ⫽ 4.26, P ⬍ 0.001). The relationship between the facial nerve function before and after treatment is shown in Table 1. Of the patients, 82.6% recovered completely (grade I) or remained with mild dysfunction only (grade II). When dealing with the group of patients with complete paralysis at presentation (grade VI), 65.2% of them recovered to grade I/II. The patient group was divided into 2 subgroups according their arrival day. Group A includes patients with a 1- to 3-day delay, and group B
include patients with a 4- to 7-day delay. Using the Mann-Whitney test, we compared the facial function before and after treatment. No significant differences were found between the 2 groups (Table 2). No immediate or late side effects were noticed during or after treatment. DISCUSSION Herpes zoster oticus is a debilitating disease responsible for 12% of cases of facial nerve paralysis.8 The facial palsy of RHS patients has a worse prognosis than that of patients with Bell’s palsy.7 Only 10% of patients with complete facial paralysis recover completely.8 The traditional treatment of RHS with high-dose corticosteroids changed with the development of the new virostatic agents, particularly acyclovir. Acyclovir has a good virostatic action on herpes group organisms with effect through interference with DNA polymerase and through inhibition of its replication. Therefore, better results are achieved when administered early in the disease. We included in our study only patients within 7 days from onset of paralysis, and no correlation was found between recovery and the day on which treatment began. Murakami et al14 divided their 80 patients into 3 subgroups. Twenty-eight patients were treated within 3 days of onset, 29 patients were treated within 3 to 7 days, and 23 patients were treated more than 7 days after onset. They found a significant difference between these groups, in favor for the early administration. Treatment should be initiated as early as possible, because complete recovery cannot take place once nerve degeneration has occurred. The parental dosage of acyclovir is 15 mg/kg per day. Because absorption from the gastrointestinal tract is only 15% to 25% of the ingested dose, higher doses are proposed for oral therapy admission. The recommended dose is 800 mg 5 times per day. Most investigators10-12 treat their patients with intravenous acyclovir, but there are reports14 of oral acyclovir administration. Murakami et al14 treated 48 of their 80 patients with oral acyclovir and found no significant difference in facial nerve outcome between intravenous and oral acyclovir treatment groups. We treated an additional 3 patients with oral acyclovir and measured their drug
Otolaryngology– Head and Neck Surgery Volume 129 Number 4
URI et al 381
Table 2. Comparison between presentation and posttreatment condition of patients with 1- to 3-day and those with 4- to 7-day interval between onset and treatment
Patient’s condition at presentation
Patient’s condition posttreatment
Delay (days)
No. of patients
Median
1-3 4-7 Total 1-3 4-7 Total
15 15 30 12 11 23
VI VI VI I I I
blood levels, but the follow-up for these patients was too short to measure recovery. There are only a few reports in the literature dealing with acyclovir, usually in combination with corticosteroids, in the treatment of RHS. Dickens et al11 reported the results of in the treatment of 8 patients. Six patients had complete paralysis, and 4 of them recovered completely. Stafford and Welch10 had similar results. We reported previously12 that of 5 patients with complete paralysis, 4 had good recovery. Of our patients in the present study, 82.6% had a recovery rate of HBGS I/II. A total of 65% obtained complete recovery. These results are much better than those with steroid treatment alone. Murakami et al14 found that 52% of patients obtained complete recovery and 81% had good recovery (grades I and II). An interesting observation was made about the relation between the audiovestibular symptoms and recovery rates. When no such symptoms exist, there is a better prognosis. The study was not controlled and double blind because we consider that unethical; it is obvious that the early treatment with prednisone and acyclovir is the treatment of choice for herpes zoster oticus. CONCLUSION Treatment of RHS patients with intravenous hydrocortisone and acyclovir become well establish fact in the last few years. In our study this treatment was given in 31 patients with overall recovery of 82.6% with no side effects. Oral treatment should be more investigated to reduce hos-
Mann-Whitney U
P
85.5
0.262
52.0
0.413
pitalization and lower the cost effectiveness of the treatment. REFERENCES
1. Hunt JR. On herpetic inflammations of the geniculate ganglion, a new syndrome and its complication. J Nerve Ment Dis 1907;34:73-96. 2. Gulderg-Moller J, Olsen S, Kettel K. Histopathology of the facial nerve in herpes zoster oticus. Arch Otolaryngol 1959;69:266-75. 3. Payten RJ, Dawes DDK. Herpes zoster of the head and neck. J Laryngol Otol 1972;86:1031-55. 4. Aviel A, Marshak G. Ramsay Hunt syndrome: a cranial polyneuropathy. Am J Otolaryngol 1982;3:61-6. 5. Wackym PA. Molecular temporal bone pathology: II. Ramsay Hunt syndrome (herpes zoster oticus). Laryngoscope 1997;107:1165-75. 6. Kanzaki J. Electrodiagnostic findings in the early stages of Bell’s palsy and Ramsay-Hunt’s syndrome. Acta Otolaryngol (Suppl) (Stockh) 1988;446(suppl):42-6. 7. Devriese PP, Moesker WH. The natural history of facial paralysis in herpes zoster. Clin Otolaryngol 1988;13:28998. 8. Robillard ZRB, Hilsinger RL Jr, Adour KK. Ramsay Hunt facial paralysis: clinical analysis of 185 patients. Otolaryngol Head Neck Surg 1986;95:292-7. 9. May M, Podvinec M, Ulrich J, et al. Idiopathic (Bell’s) palsy, herpes zoster cephalicus and other facial nerve disorders of viral origin. In: May M, editor. The facial nerve. New York: Thieme-Stratton; 1986. p. 365-99. 10. Stafford FW, Welch AR. The use of acyclovir in Ramsay Hunt syndrome. J Laryngol Otol 1986;100:337-40. 11. Dickins JRE, Smith JT, Graham SS. Herpes zoster oticus: treatment with intravenous acyclovir. Laryngoscopi 1988;98:776-9. 12. Uri N, Greenberg E, Kitzes-Cohen R. et al. Herpes zoster oticus: treatment with acyclovir. Ann Otol Rhinol Laryngol 1992;101:161-2. 13. House JW, Brackmann DE. Facial nerve grading system. Otolaryngol Head Neck Surg 1985;93:146-7. 14. Murakami S, Hato N, Horluchi J. Treatment of Ramsay Hunt syndrome with acyclovir-prednisone: significance of early diagnosis and treatment. Ann Neurol 1997;41: 353-7.