Atypical Presentation of a Common Disease: Shingles of the Larynx *Sarah Hosseini, †,‡Faisal Zawawi, and †Jonathan Young, *yMontreal, Quebec, Canada, and zJeddah, Saudi Arabia Summary: Objective. Herpes zoster is a neurocutaneous disease resulting from the reactivation of endogenous varicella-zoster virus (VZV) in dorsal sensory or cranial nerve ganglia. Rarely, this infection manifests without the characteristic dermatomal rash, a condition termed zoster sine herpete. Viral spreading of herpes zoster in the head and neck may manifest as various signs and symptoms because of the multiple possible combinations of cranial neuropathies. With only six cases reported in the English literature up to now, isolated neuropathies of the vagus nerve in the absence of cutaneous lesions tend to be misdiagnosed as idiopathic laryngeal paralysis. Methods. We report a case of herpes zoster of the larynx in an 80-year-old man presenting with sore throat, dysphagia, and hoarseness. Results. Endoscopic examination revealed unilateral vocal fold paralysis, pooling of secretions, and mucosal vesicles of the hemilarynx. After the diagnosis of VZV infection with polymerase chain reaction (PCR) testing, the patient was treated with valacyclovir and corticosteroids, leading to complete recovery after 2 months. Conclusions. Herpes zoster of the larynx is an uncommon condition that should be included in the differential diagnosis of laryngeal paralysis of idiopathic cause. We recommend performing a thorough examination of the pharyngolaryngeal structures and ordering PCR testing as the diagnostic method of choice. Key Words: Varicella-zoster virus–Herpes zoster–Larynx–Cranial neuropathy–Polymerase chain reaction. INTRODUCTION Varicella-zoster virus (VZV) infection produces two distinct types of clinical manifestations. The first contact with this virus, transmitted by airborne viral particles shed from the skin of an infected person, results in varicella (chickenpox).1 It is a highly contagious and generally benign disease of childhood but may also affect nonimmune adults. The chickenpox rash is characterized by vesicular lesions of different stages of development, first appearing on the face, middle of the trunk, or scalp and then spreading to the extremities. After resolution of symptoms, VZV travels to the dorsal root ganglia of the spinal cord via sensory fibers, where it remains dormant for years. Herpes zoster (shingles) results from reactivation of latent VZV, usually secondary to impaired cellular immunity. Clinically, this form of the disease is characterized by a painful and/or burning sensation, accompanied by an erythematous maculopapular rash, both of which follow a strict unilateral dermatomal distribution, pathognomonic of this condition.2–4 Depending on which nerves are affected by viral spreading, multiple cranial neuropathies can result from shingles. However, only a few reports in the literature have been published on cases of zoster sine herpete (ZSH) restricted to the distribution of the vagus nerve. Here, we report a case of ZSH in an immunocompetent patient with unilateral vocal fold paralysis.
Accepted for publication October 16, 2014. From the *Faculty of Medicine, McGill University, Montreal, Quebec, Canada; yDepartment of Otolaryngology – Head and Neck Surgery, McGill University, Montreal, Quebec, Canada; and the zDepartment of Otolaryngology, King Abdulaziz University, Jeddah, Saudi Arabia. Address correspondence and reprint requests to Sarah Hosseini, Faculty of Medicine, McGill University, 4157 Marcil, Montreal, Quebec H4A 2Z7, Canada. E-mail: sarah.f. [email protected] Journal of Voice, Vol. -, No. -, pp. 1-3 0892-1997/$36.00 Ó 2014 The Voice Foundation http://dx.doi.org/10.1016/j.jvoice.2014.10.010
CASE REPORT An 80-year-old man was referred to the department of otolaryngology – head and neck surgery in a tertiary care hospital with a 2-day history of sore throat, dysphagia, and hoarseness. The patient denied dyspnea and could form complete sentences despite his symptoms. He did not present any constitutional symptoms or immunosuppression risk factors and denied sick contacts in his entourage. He recalled receiving the influenza vaccine 1 month before admission. This patient was known for hypertension, long-standing dyslipidemia, and benign prostatic hyperplasia, as well as for a right parathyroid adenoma discovered 30 years ago. He was an ex-smoker with a 60 pack-year history and stopped smoking 30 years ago. On physical examination, no evidence of skin rash was observed in the head and neck region. Flexible fiberoptic laryngoscopy revealed a paralysis of the right vocal fold fixed in the paramedian position, secretions pooling in the right pyriform sinus, and whitish mucosal lesions localized to the right epiglottic and supraglottic regions (Figure 1A and B). A clear delineation was noted in the interarytenoid region, where the lesions were present on the right and markedly absent on the left (Figure 1B). On the laryngeal surface of the epiglottis, the lesions crossed the midline but were scarce. Supraglottic swelling and erythema were also noted (Figure 2). Neck computed tomography with enhancement revealed mild thickening of the epiglottis without any prevertebral soft-tissue thickening. Furthermore, mild asymmetric enlargement of the right laryngeal ventricle and slight asymmetry of the right pyriform sinus consistent with the laryngoscopy findings were seen. No mass lesions other than the known parathyroid adenoma (unchanged in size since the last CT performed in 2011) were observed, ruling out tumor mass effect as a possible cause of the vagus nerve palsy. Hematology testing showed a white blood cell count of 8400/mL with a differential comprising a low lymphocyte count (15.3%), a normal neutrophil count (69.7%), and a high monocyte count (13.6%).
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Journal of Voice, Vol. -, No. -, 2014
FIGURE 1. Laryngoscopy reveals a right vocal fold fixed in the paramedian position (arrow on A). Whitish mucosal lesions (asterisks on A and B) can be observed in the supraglottic region on the right only, with a clear delineation in the interarytenoid region (arrow on B).
Five days after the admission, the patient complained of severe dysphagia. A barium swallow study of the upper aerodigestive tract revealed significant aspiration with barium entering the trachea. A chest x-ray performed immediately after showed barium lining the walls of trachea, in keeping with aspiration. A laryngoscopic examination after barium swallow revealed new epiglottic lesions with an acute onset over 48 hours. The following day, a dynamic study performed in conjunction with a speech pathologist revealed abnormal swallowing mechanism with poor propulsion of liquids and semisolids by the tongue. A large residual volume was also present within the esophagus. The results of these preliminary investigations pointed toward the diagnosis of an infectious process (Candida, herpes simplex virus [HSV], or VZV infection) as the most likely cause of this patient’s condition. A sample of exudates taken from the pharyngeal mucosal lesions was obtained for fungal and viral (VZVand HSV) cultures. While awaiting microbiology results, fluconazole 200 mg by mouth daily and valacyclovir 1 g by mouth daily were empirically administered. To reduce the pain and the risk of developing postherpetic neuralgia,3 a tapered dose of prednisone, starting at 50 mg, was given by mouth daily for 5 days.
FIGURE 2. The supraglottic region shows diffuse swelling and erythema. Epiglottic mucosal plaques are mostly localized to the right side; one lesion is present on the left (asterisk).
Two days later, the patient reported that the hoarseness and swallowing dysfunction had improved. Polymerase chain reaction (PCR) testing came back positive for VZV and negative for both HSV-1 and HSV-2. Fungal growth was also negative. Consequently, the patient was taken off fluconazole, and his valacyclovir regimen was revised to 1 g by mouth three times a day for 7 days. Although the patient had improved odynophagia after 4 days, the dysphagia persisted for another 2 weeks. Nonetheless, healing of the mucosal lesions was noted, and the right vocal fold dysfunction had also diminished in severity. One month later, the patient’s condition completely resolved. DISCUSSION VZV reactivation most commonly occurs secondary to an immunocompromised state, especially in patients younger than 50 years.5 Advanced age, psychological stress, and physical trauma can also act as triggers.6 The sharp increase in the incidence of herpes zoster among patients aged 50–60 years is most likely related to decreased VZV-specific cell-mediated immunity with increasing age.3 This is the most probable mechanism by which the patient described in this case report developed herpes zoster as he did not present any other known risk factors. Herpes zoster presenting as cranial neuropathies with mucosal lesions, but lacking cutaneous involvement or evidence of herpes zoster oticus, is uncommon. In fact, only 12 such cases have been documented in the English literature.1,7 Among these reported cases, half involve herpes zoster of the larynx limited to cranial nerve X palsy (Table 1) as in our case presentation. The vagus nerve innervates the larynx via its superior laryngeal and recurrent laryngeal branches. The former further divides into external and internal branches. The external branch supplies motor innervation to the cricothyroid muscle, whereas the internal branch brings sensory innervation to the mucosa of the vocal folds and of most supraglottic structures. The recurrent laryngeal nerve, which supplies all the intrinsic laryngeal musculature except for the cricothyroid, causes vocal fold paralysis when injured. Because it needs to travel a long distance from the Xth cranial nerve ganglion to the pharyngolaryngeal region, the recurrent laryngeal nerve is the most vulnerable of all vagus nerve branches.2
Sarah Hosseini, et al
3
Shingles of the Larynx
TABLE 1. Previously Reported Cases of VZV Infection of the Larynx With Herpetic Mucosal Eruptions but Without Skin Manifestations and Confined to Cranial Nerve X Palsy in the English Literature Patient No.
Age/Sex
Our case
80/M
1
70/F
2
60/M
3
73/M
4
74/M
5
53/F
6
97/M
Symptoms on Admission Sore throat, dysphagia, hoarseness Odynophagia, otalgia Sore throat, dysphagia, hoarseness Sore throat, hiccups Odynophagia, hoarseness, prelaryngeal skin erythema Sore throat, odynophagia Odynophagia, dysphagia, hoarseness
Diagnostic Method PCR Serology (IgM) Serology (IgG) Serology (CF) Serology (IgG)
Serology (IgM + IgG) Serology (IgG)
Treatment Valacyclovir, corticosteroids Acyclovir, corticosteroids Corticosteroids only Acyclovir, corticosteroids Valacyclovir
No antiviral or corticosteroids Valacyclovir, corticosteroids
Condition at Final Follow-Up 2 mo – complete recovery 4 mo – vocal palsy persisted 3 mo – complete recovery 3 wk – complete recovery No description
1 mo – complete recovery 2 wk – vocal palsy improved
Abbreviations: CF, complement fixation; F, female; IgG, immunoglobulin G; IgM, immunoglobulin M; M, male; PCR, polymerase chain reaction.
The patient in our case presented with mucosal lesions confined to the vagal sensory territory and right vocal fold paralysis, suggesting that VZV infection spreads to both the superior and recurrent branches of the right vagus nerve. Just like ZSH affecting the facial nerve can mimic diseases such as Bell’s palsy, ZSH affecting the vagus nerve can be misdiagnosed as idiopathic laryngeal paralysis.8 Hence, a thorough examination of the pharyngolaryngeal mucosa should be performed when faced with an unexplained paralysis of the vagus nerve.9 On top of the fact that cases of ZSH are more difficult to diagnose compared with zoster with skin manifestations, it is believed that herpetic eruptions of the mucosa tend to disappear quickly,2 which may cause their presentation to be clinically indistinguishable from idiopathic laryngeal paralysis. Consequently, although a clinical diagnosis is sufficient in typical presentations of herpes zoster, the most reliable method to distinguish VZV infection from idiopathic laryngeal paralysis, in the absence of cutaneous lesions, is by serologic testing or detection of VZV DNA by PCR.8 Because the former method requires paired sera for the VZV reactivation to be confirmed, it takes up to 3 weeks for the final diagnosis to be made.8 In contrast, PCR results can be obtained much faster, and the sensitivity approaches 100%.3 The importance of finding a diagnosis early in the presentation of the disease lies in the fact that early administration of antiviral drugs gives rise to better outcome. Hence, we recommend PCR testing over serology when both options are available. CONCLUSION We described an unusual presentation of VZV reactivation confined to the right hemilarynx and causing unilateral vocal fold paralysis. Only six similar cases have been reported in the English literature up to now. While neurotropic viruses
such as VZV tend to cause multiple cranial palsies, isolated neuropathies, especially of the Xth cranial nerve, are rare manifestations of these viruses that consequently tend to be misdiagnosed as idiopathic. Therefore, whenever such cases arise, we recommend performing a thorough examination of the pharyngolaryngeal structures and ordering PCR testing as the diagnostic method of choice. CONSENT Informed consent was obtained from the patient for the publication of this report and any accompanying images, and thus, formal institutional review board was not required after consultation with our hospitals’ research ethics committee. REFERENCES 1. Lin YY, Kao CH, Wang CH. Varicella zoster virus infection of the pharynx and larynx with multiple cranial neuropathies. Laryngoscope. 2011;121:1627–1630. 2. Chitose SI, Umeno H, Hamakawa S, Nakashima T, Shoji H. Unilateral associated laryngeal paralysis due to varicella-zoster virus: virus antibody testing and videofluoroscopic findings. J Laryngol Otol. 2008;122:170–176. 3. Yoshikawa TT, Schmader K. Herpes zoster in older adults. Clin Infect Dis. 2001;32:1481–1486. 4. Pinto JA, Pinto HC, Ramalho Jda R. Laryngeal herpes: a case report. J Voice. 2002;16:560–563. 5. Shihada R, Brodsky A, Luntz M. Laryngeal mass with multiple cranial neuropathies as a presenting sign for varicella zoster infection. Dysphagia. 2010; 25:153–155. 6. Choi JH. Two cases of pharyngolaryngeal zoster advanced to multiple cranial neuropathy. Am J Otol. 2013;34:369–372. 7. Carter JM, Cai D, Moore BA. Herpes zoster of the larynx. Poster presented at: Triological Society: Combined Sections Meeting. January 24-26, 2013; Scottsdale, AZ. 8. Fujiwara K, Furuta Y, Fukuda S. A case of associated laryngeal paralysis caused by varicella zoster virus without eruption. Case Rep Med. 2014; 2014:916265. 9. Lewis GW. Zoster sine herpete. Br Med J. 1958;2:418–421.
Accepted for publication October 16, 2014. From the *Faculty of Medicine, McGill University, Montreal, Quebec, Canada; yDepartment of Otolaryngology – Head and Neck Surgery, McGill University, Montreal, Quebec, Canada; and the zDepartment of Otolaryngology, King Abdulaziz University, Jeddah, Saudi Arabia. Address correspondence and reprint requests to Sarah Hosseini, Faculty of Medicine, McGill University, 4157 Marcil, Montreal, Quebec H4A 2Z7, Canada. E-mail: sarah.f. [email protected] Journal of Voice, Vol. -, No. -, pp. 1-3 0892-1997/$36.00 Ó 2014 The Voice Foundation http://dx.doi.org/10.1016/j.jvoice.2014.10.010
CASE REPORT An 80-year-old man was referred to the department of otolaryngology – head and neck surgery in a tertiary care hospital with a 2-day history of sore throat, dysphagia, and hoarseness. The patient denied dyspnea and could form complete sentences despite his symptoms. He did not present any constitutional symptoms or immunosuppression risk factors and denied sick contacts in his entourage. He recalled receiving the influenza vaccine 1 month before admission. This patient was known for hypertension, long-standing dyslipidemia, and benign prostatic hyperplasia, as well as for a right parathyroid adenoma discovered 30 years ago. He was an ex-smoker with a 60 pack-year history and stopped smoking 30 years ago. On physical examination, no evidence of skin rash was observed in the head and neck region. Flexible fiberoptic laryngoscopy revealed a paralysis of the right vocal fold fixed in the paramedian position, secretions pooling in the right pyriform sinus, and whitish mucosal lesions localized to the right epiglottic and supraglottic regions (Figure 1A and B). A clear delineation was noted in the interarytenoid region, where the lesions were present on the right and markedly absent on the left (Figure 1B). On the laryngeal surface of the epiglottis, the lesions crossed the midline but were scarce. Supraglottic swelling and erythema were also noted (Figure 2). Neck computed tomography with enhancement revealed mild thickening of the epiglottis without any prevertebral soft-tissue thickening. Furthermore, mild asymmetric enlargement of the right laryngeal ventricle and slight asymmetry of the right pyriform sinus consistent with the laryngoscopy findings were seen. No mass lesions other than the known parathyroid adenoma (unchanged in size since the last CT performed in 2011) were observed, ruling out tumor mass effect as a possible cause of the vagus nerve palsy. Hematology testing showed a white blood cell count of 8400/mL with a differential comprising a low lymphocyte count (15.3%), a normal neutrophil count (69.7%), and a high monocyte count (13.6%).
2
Journal of Voice, Vol. -, No. -, 2014
FIGURE 1. Laryngoscopy reveals a right vocal fold fixed in the paramedian position (arrow on A). Whitish mucosal lesions (asterisks on A and B) can be observed in the supraglottic region on the right only, with a clear delineation in the interarytenoid region (arrow on B).
Five days after the admission, the patient complained of severe dysphagia. A barium swallow study of the upper aerodigestive tract revealed significant aspiration with barium entering the trachea. A chest x-ray performed immediately after showed barium lining the walls of trachea, in keeping with aspiration. A laryngoscopic examination after barium swallow revealed new epiglottic lesions with an acute onset over 48 hours. The following day, a dynamic study performed in conjunction with a speech pathologist revealed abnormal swallowing mechanism with poor propulsion of liquids and semisolids by the tongue. A large residual volume was also present within the esophagus. The results of these preliminary investigations pointed toward the diagnosis of an infectious process (Candida, herpes simplex virus [HSV], or VZV infection) as the most likely cause of this patient’s condition. A sample of exudates taken from the pharyngeal mucosal lesions was obtained for fungal and viral (VZVand HSV) cultures. While awaiting microbiology results, fluconazole 200 mg by mouth daily and valacyclovir 1 g by mouth daily were empirically administered. To reduce the pain and the risk of developing postherpetic neuralgia,3 a tapered dose of prednisone, starting at 50 mg, was given by mouth daily for 5 days.
FIGURE 2. The supraglottic region shows diffuse swelling and erythema. Epiglottic mucosal plaques are mostly localized to the right side; one lesion is present on the left (asterisk).
Two days later, the patient reported that the hoarseness and swallowing dysfunction had improved. Polymerase chain reaction (PCR) testing came back positive for VZV and negative for both HSV-1 and HSV-2. Fungal growth was also negative. Consequently, the patient was taken off fluconazole, and his valacyclovir regimen was revised to 1 g by mouth three times a day for 7 days. Although the patient had improved odynophagia after 4 days, the dysphagia persisted for another 2 weeks. Nonetheless, healing of the mucosal lesions was noted, and the right vocal fold dysfunction had also diminished in severity. One month later, the patient’s condition completely resolved. DISCUSSION VZV reactivation most commonly occurs secondary to an immunocompromised state, especially in patients younger than 50 years.5 Advanced age, psychological stress, and physical trauma can also act as triggers.6 The sharp increase in the incidence of herpes zoster among patients aged 50–60 years is most likely related to decreased VZV-specific cell-mediated immunity with increasing age.3 This is the most probable mechanism by which the patient described in this case report developed herpes zoster as he did not present any other known risk factors. Herpes zoster presenting as cranial neuropathies with mucosal lesions, but lacking cutaneous involvement or evidence of herpes zoster oticus, is uncommon. In fact, only 12 such cases have been documented in the English literature.1,7 Among these reported cases, half involve herpes zoster of the larynx limited to cranial nerve X palsy (Table 1) as in our case presentation. The vagus nerve innervates the larynx via its superior laryngeal and recurrent laryngeal branches. The former further divides into external and internal branches. The external branch supplies motor innervation to the cricothyroid muscle, whereas the internal branch brings sensory innervation to the mucosa of the vocal folds and of most supraglottic structures. The recurrent laryngeal nerve, which supplies all the intrinsic laryngeal musculature except for the cricothyroid, causes vocal fold paralysis when injured. Because it needs to travel a long distance from the Xth cranial nerve ganglion to the pharyngolaryngeal region, the recurrent laryngeal nerve is the most vulnerable of all vagus nerve branches.2
Sarah Hosseini, et al
3
Shingles of the Larynx
TABLE 1. Previously Reported Cases of VZV Infection of the Larynx With Herpetic Mucosal Eruptions but Without Skin Manifestations and Confined to Cranial Nerve X Palsy in the English Literature Patient No.
Age/Sex
Our case
80/M
1
70/F
2
60/M
3
73/M
4
74/M
5
53/F
6
97/M
Symptoms on Admission Sore throat, dysphagia, hoarseness Odynophagia, otalgia Sore throat, dysphagia, hoarseness Sore throat, hiccups Odynophagia, hoarseness, prelaryngeal skin erythema Sore throat, odynophagia Odynophagia, dysphagia, hoarseness
Diagnostic Method PCR Serology (IgM) Serology (IgG) Serology (CF) Serology (IgG)
Serology (IgM + IgG) Serology (IgG)
Treatment Valacyclovir, corticosteroids Acyclovir, corticosteroids Corticosteroids only Acyclovir, corticosteroids Valacyclovir
No antiviral or corticosteroids Valacyclovir, corticosteroids
Condition at Final Follow-Up 2 mo – complete recovery 4 mo – vocal palsy persisted 3 mo – complete recovery 3 wk – complete recovery No description
1 mo – complete recovery 2 wk – vocal palsy improved
Abbreviations: CF, complement fixation; F, female; IgG, immunoglobulin G; IgM, immunoglobulin M; M, male; PCR, polymerase chain reaction.
The patient in our case presented with mucosal lesions confined to the vagal sensory territory and right vocal fold paralysis, suggesting that VZV infection spreads to both the superior and recurrent branches of the right vagus nerve. Just like ZSH affecting the facial nerve can mimic diseases such as Bell’s palsy, ZSH affecting the vagus nerve can be misdiagnosed as idiopathic laryngeal paralysis.8 Hence, a thorough examination of the pharyngolaryngeal mucosa should be performed when faced with an unexplained paralysis of the vagus nerve.9 On top of the fact that cases of ZSH are more difficult to diagnose compared with zoster with skin manifestations, it is believed that herpetic eruptions of the mucosa tend to disappear quickly,2 which may cause their presentation to be clinically indistinguishable from idiopathic laryngeal paralysis. Consequently, although a clinical diagnosis is sufficient in typical presentations of herpes zoster, the most reliable method to distinguish VZV infection from idiopathic laryngeal paralysis, in the absence of cutaneous lesions, is by serologic testing or detection of VZV DNA by PCR.8 Because the former method requires paired sera for the VZV reactivation to be confirmed, it takes up to 3 weeks for the final diagnosis to be made.8 In contrast, PCR results can be obtained much faster, and the sensitivity approaches 100%.3 The importance of finding a diagnosis early in the presentation of the disease lies in the fact that early administration of antiviral drugs gives rise to better outcome. Hence, we recommend PCR testing over serology when both options are available. CONCLUSION We described an unusual presentation of VZV reactivation confined to the right hemilarynx and causing unilateral vocal fold paralysis. Only six similar cases have been reported in the English literature up to now. While neurotropic viruses
such as VZV tend to cause multiple cranial palsies, isolated neuropathies, especially of the Xth cranial nerve, are rare manifestations of these viruses that consequently tend to be misdiagnosed as idiopathic. Therefore, whenever such cases arise, we recommend performing a thorough examination of the pharyngolaryngeal structures and ordering PCR testing as the diagnostic method of choice. CONSENT Informed consent was obtained from the patient for the publication of this report and any accompanying images, and thus, formal institutional review board was not required after consultation with our hospitals’ research ethics committee. REFERENCES 1. Lin YY, Kao CH, Wang CH. Varicella zoster virus infection of the pharynx and larynx with multiple cranial neuropathies. Laryngoscope. 2011;121:1627–1630. 2. Chitose SI, Umeno H, Hamakawa S, Nakashima T, Shoji H. Unilateral associated laryngeal paralysis due to varicella-zoster virus: virus antibody testing and videofluoroscopic findings. J Laryngol Otol. 2008;122:170–176. 3. Yoshikawa TT, Schmader K. Herpes zoster in older adults. Clin Infect Dis. 2001;32:1481–1486. 4. Pinto JA, Pinto HC, Ramalho Jda R. Laryngeal herpes: a case report. J Voice. 2002;16:560–563. 5. Shihada R, Brodsky A, Luntz M. Laryngeal mass with multiple cranial neuropathies as a presenting sign for varicella zoster infection. Dysphagia. 2010; 25:153–155. 6. Choi JH. Two cases of pharyngolaryngeal zoster advanced to multiple cranial neuropathy. Am J Otol. 2013;34:369–372. 7. Carter JM, Cai D, Moore BA. Herpes zoster of the larynx. Poster presented at: Triological Society: Combined Sections Meeting. January 24-26, 2013; Scottsdale, AZ. 8. Fujiwara K, Furuta Y, Fukuda S. A case of associated laryngeal paralysis caused by varicella zoster virus without eruption. Case Rep Med. 2014; 2014:916265. 9. Lewis GW. Zoster sine herpete. Br Med J. 1958;2:418–421.
