Clinics in Dermatology (2014) 32, 424–429
Herpes zoster as a systemic disease Ivan Staikov, MD, PhD a,⁎, Neyko Neykov, MD a , Branka Marinovic, MD, PhD b , Jasna Lipozenčić, MD, PhD b , Nikolai Tsankov, MD, PhD, MSc a a
Departments of Neurology and Dermatology, Tokuda Hospital Sofia, Bulgaria Department of Dermatology, Medical Faculty, Zagreb, Croatia
b
Abstract Herpes zoster (shingles, zona) is a viral infection commonly affliccting the skin and the nervous system with an overall occurring rate of 3 to 5 cases per 1000 persons per year, with higher rates in middle or later life. With the advancement of medicine, more and more case reports have started to emerge showing different incidences of VZV, some new localizations, clinical presentations, and complications, which break the well-known fact that “VZV affects the skin and nervous system.” Skin lesions are the most important ones for the early and exact diagnosis of herpes zoster (HZ), due to its visibility and well-defined clinical picture of lesions. The most frequent condition following the acute herpes zoster eruption is postherapeutic neuralgia (PHN). There have been other reports of the disease with otorinolaryngologic complications and ophthalmologic ones, such as ophthalmoparesis/ plegia. There have also been reports of delayed contralateral hemiparesis/hemiplegia following the infection, as a manifestation of vaculitis due to a direct VZV invasion of the cerebral arteries. Encephalitis and destructive myelitis is similarly rare, but a serious complication. Some authors found that patients with inflammatory bowel disease are at a significantly increased risk for herpes zoster. As a gastroenterologic complication, there have been several instances of HZV infection with symptoms resembling an acute abdomen. The diagnosis is hard to pinpoint, and a vast array of examinations are required to identify it, sometimes even posthumously. Nephrologic representations and complications have also been reported. With more and more skin diseases being acknowledged as systemic ones, this viral infection is a more likely candidate for the same title. © 2014 Elsevier Inc. All rights reserved.
Introduction Herpes zoster (shingles, zona) is a viral infection commonly afflicting the skin and the nervous system with an overall occurring rate of 3 to 5 cases per 1000 persons per year, with higher rates in middle or later life.1 Especially at risk are immunocompromised patients, the incidence in whom is about 20 times higher. Some historical features of herpes zoster show that the neurologic implications of the segmental distribution of the eruption were recognized in 1831. The first description of ⁎ Corresponding author. Tel.: +359 88 49 33 001; fax: +359 2 403 44 03. E-mail address: [email protected] (I. Staikov). 0738-081X/$ – see front matter © 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clindermatol.2013.11.010
the inflammatory changes in the ganglia and related portions of the spinal nerves were made in 1862. In 1909, the concept that varicella and zoster are caused by the same agent was introduced.1 The virus that causes herpes zoster is the varicella zoster virus (VZV), the causative agent of varicella.2 VZV is a large, double strained DNA-containing virus, enclosed in a protein envelope that is similar in structure to the virus of herpes simplex. 1,2 The infection is usually clinically characterized by a skin eruption preceded and followed by pain in the distribution of the affected root ganglia. Primary VZV infection, which usually occurs in childhood, results in chickenpox (varicella), after which the virus becomes latent in the cranial nerve ganglia, dorsal root ganglia, and
Herpes zoster autonomic ganglia along the entire neuraxis. Later, as cellmediated immunity to VZV declines with age or is caused by immunosuppression (such as in organ-transplant recipients or in patients with cancer or HIV), VZV can reactivate and cause zoster. With the advancement of medicine, more and more case reports have started to emerge, showing different incidences of VZV, some new localizations, clinical presentations, and complications that break the well-known fact that “VZV affects the skin and nervous system.” Skin lesions are the most important ones for the early and exact diagnosis of herpes zoster (HZ) due to its visibility and well-defined clinical picture of lesions. Varicella zoster virus (VZV) moves down the nerve axon and causes skin lesions in the corresponding dermatome. Basically, skin lesions are determined as a dermatome eruption with pain, but clinically they are characterized with different phases3: • Preeruptive phase • Acute eruptive phase • Chronic phase
Preeruptive phase (preherpetic neuralgia) This prodromal period is characterized by sensory nerves phenomena, including paresthesias, pain, burning, or itching in the affected area. Usually, this period lasts 48 to 72 hours but could be extended to a week. Pain may resemble headache, brachial neuritis, cardiac pain, appendicitis, etc. Malaise, myalgia, headache, photophobia, and fever can be present along with the main neurologic symptoms.
Acute eruptive phase
425 localized in the same area as the skin lesions. Pain can be mild to severe often with a burning sensation and can last for a long period after the eruption has disappeared. Pain is described as stinging, tingling, aching, or burning. Pruritus is usually mild.
Clinical forms Disseminated herpes zoster The eruption in disseminated herpes zoster is localized within the borders of one or more primarily affected dermatomes.4 These extradermatomal vesicles occur a week after the onset of classic dermatomal herpes zoster. Disseminated herpes zoster occurs in approximately 2% of the zoster cases. This clinical form often develops in patients with depressed cellmediated immunity, which can be caused by various underlying clinical situations, including malignancies, radiation therapy, cancer chemotherapy, organ transplants, and long-term use of systemic corticosteroids.
Recurrent herpes zoster In one study, the frequency of herpes zoster (HZ) recurrence in a community population was higher than previously reported.5 In this study, 1669 patients with a medically documented episode of HZ were investigated. Out of a total number of patients, 95 of them had 105 recurrences. The Kaplan-Meier estimate of the recurrence rate at 8 years was 6.2%. With a maximum follow-up of 12 years, the time between HZ episodes in the same person varied from 96 days to 10 years.
Zoster sine herpete After the prodromal period, typical skin lesions appear involving one or a few neighboring dermatomes. At first, erythematous macular, papular or urticarial-like lesions become visible on the skin, but they quickly turn to vesicles. The typical vesicles are grouped in a herpetiform pattern on the erythematous skin. The size of the vesicles is between 1 to 2 mm, but some of them can become confluent. Skin lesions are always distributed unilaterally in a stripe or beltlike pattern. They do not cross the midline. In the beginning, the vesicles are clear, filled with serous fluid. After 3 to 5 days, the vesicles become hemorrhagic and thereafter dry out with brownish crusts. A new eruption may appear over a period of 3 to 4 days. These new lesions appear in the same area and have the same evolutionary polymorphism. Patients are infectious until the vesicles convert to crusts. Enlarged regional lymph nodes can be observed. The eruption heals within two to four weeks. Scarring is rare, usually only if there is a superinfection. The subjective symptoms are usually pain, pruritus, and/or hyperesthesia
Patients with this clinical form represent the entire symptom characteristic for herpes zoster except the typical eruption. Patients experience pain and weakness in a dermatomal distribution, but they have no skin signs, or in rare cases only erythematous macules or plaques with no vesicles.
Herpes zoster and immunodeficiency HZ rates of 29.4 to 51.5 per 1000 person/year have been reported among adults infected with the human immunodeficiency virus. In this form, due to severe immunodeficiency, the eruption often crosses the midline (Figure 1). In addition, higher rates have also been reported in persons with systemic lupus erythematosus, rheumatoid arthritis, granulomatosis with polyangiitis (Wegener), and inflammatory bowel disease.6
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Herpes zoster and impetiginization of the lesions
Chronic phase (postherapeutic neuralgia)
This form is the result of a secondary bacterial infection at the site of the eruption (typically streptococcal or staphylococcal). Necrotizing fasciitis is a possible complication.
The most frequent condition following the acute herpes zoster eruption is postherapeutic neuralgia (PHN). PHN may affect cranial as well as peripheral nerves. The estimated incidence of PHN varies from country to country from 2.0 cases in 1000 people in the United States9 and 8.99/1000 in European countries, such as France.10 PHN is defined as pain at different time intervals after regression of the lesions of HZ in the affected dermatome. To confirm the diagnosis, there has to be daily pain that persists for 3 to 6 months after onset.11 PHN presents as chronic neuropathic pain in a dermatome with unpleasant sensations, such as “throbbing,” “shooting,” “stabbing,” etc. and a paroxysmal lancinating pain, which usually manifests every day and has a big impact on the patient’s quality of life.12 Current treatment involves opioids, tricyclic antidepressants, anticonvulsants, and lidocaine patches, which result only with partial pain relief, but the pain usually persists for months or years. The patient’s response to the treatment wildly varies, and the physician has to take into account and weigh out the possible various adverse effects of the medications for the pain relief and resulting quality of life.13 Any dermatome may be involved, but the most commonly involved are the thoracic dermatomes, particularly T5-T10, presenting in more than two-thirds of cases, followed by the craniocervical regions.1 Sometimes, a focal, asymmetric neurogenic weakness may occur in an extremity affected by cutaneous zoster. Such weakness is due to a lesion of the ventral nerve root, in close proximity to the inflammation in the initiating dorsal ganglion.14 Antiinflammatory treatment is usually administered together with antiviral treatment. Functional motor recovery appears in about 75% of cases within 1 to 2 years.
Wolf’s isotopic response (phenomenon) Inflammatory skin lesions following zoster infection can occur within the affected dermatome. Wolf's isotopic response may be explained as a special subtype of the Koebner phenomenon, in which one skin disease triggers another one.7
Herpes zoster after varicella-zoster vaccination 8 Varicella vaccine contains live attenuated VZV, which causes latent infection. The attenuated vaccine virus can reactivate the virus and cause herpes zoster. People who get vaccinated against varicella may develop herpes zoster later in life; however, their risk is lower than that of the people who were infected with the wild-type VZV. Vaccination also reduces the severity and duration of the disease, as well as its most common complication—postherapeutic neuralgia.
Neurologic and otorinolaryngological involvement
Fig. 1
Herpes zoster in HIV-positive patient.
A neurologic and otorinolaryngologic complication of VZV manifests as Ramsay Hunt syndrome (RHS). RHS is a peripheral facial nerve palsy, usually accompanied by a herpes zoster eruption in the external auditory canal, other parts of the cranial integument, and mucous membrane of the oropharynx, and affects the geniculate ganglion.15 Although similar to Bell’s palsy, its clinical symptoms are more heavily manifested, and there is a higher likelihood of multiple cranial nerve involvement.16 Compared with Bell’s palsy, patients with this syndrome often have more severe paralysis at the onset and are less likely to recover completely. Sometimes, due to the involvement of the vestibulocochlear nerve, RHS is accompanied by vertigo, tinnitus, and unilateral hearing loss,17 although there are reports of the involvement of other cranial nerves.18 Loss of taste over the anterior two-thirds of the tongue occurs in more than 50% of patients.2 There are several authors pinpointing VZV infection with RHS as a primarily
Herpes zoster otorinolaryngologic condition with a secondary dissemination toward the cranial nerves.19–21 Treatment involves usage of acyclovir and prednisone for a better outcome and prognosis.22
427 may cause asymmetric paraparesis, sensory lost, sphincter disturbances, and Brown-Sequard syndrome.1 Polyneuritis of the Guillain-Barre type has been also reported as a consequence of herpes zoster.2
Ophthalmologic involvement Gastrointestinal involvement There have been reports of ophthalmoparesis/plegia after herpes zoster ophthalmicus (HZO). Involvement of the trigeminal ganglion occurs in about 20% of patients and the first division—ophthalmic is the most frequently affected.2 Ophthalmoplegia as part of the sequela of HZO has typically been described as a late complication, often up to 2 months after the initial herpetic eruption.23 HZO involves not only the cranial nerve but also affects and impairs vision and causes damage to the eye bulbi and pupilae, as well as a pure ophthalmologic complication.24,25 Another complication of ophthalmic zoster is acute contralateral hemiplegia and ipsilateral hemisphere signs, such as aphasia, that can occur weeks or months later after HZO.2
Vasculopathy There have been reports of symptoms of delayed contralateral hemiparesis/hemiplegia following a VZV infection. This is a manifestation of vaculitis due to a direct VZV invasion of the cerebral arteries.26,27 This VZV vasculopathy affects both immunocompetent and immunocompromised patients, occurs after zoster or varicella, and can be either unifocal or multifocal. VZV vasculopathy among other conditions can cause ischemic stroke, potentiate a formation of an aneurysm, and sometimes indirectly cause subarachnoid and intraparenchimal cerebral hemorrhaging.28
Encephalitis Encephalitis is a rare but serious complication of herpes zoster. Although rare, it may occur in up to 5% of patients with HZ.29 A few studies have examined the brain changes and cognitive outcomes associated with herpes zoster encephalitis. They show variability in the brain regions affected, severity of neurologic damage, and cognitive deficit. Symptoms vary, the initial ones usually consist of headache, vomiting, fever, and altered sensory feel.30
Myelitis Destructive myelitis is similarly rare, but serious complication mainly of thoracic zoster. The signs of spinal cord involvement appear 15 to 21 days after the eruption and
Some authors have found that patients with inflammatory bowel disease are at a significantly increased risk for herpes zoster.31 They did a retrospective cohort and nested case– control study and analyzed more than 108,000 patients with inflammatory bowel disease and 430,000 matched controls. The overall annual incidence of herpes zoster per 100,000 person-years was 734 among inflammatory bowel disease patients, compared with 437 in noninflammatory bowel disease patients (incidence rate ratio = 1.68). This study gives evidences for an elevated risk for HZ in inflammatory bowel disease patients. According to the same paper, treatment with thiopurines, corticosteroids, and biologic antitumor necrosis factor–alpha (anti-TNF) agents was independently associated with an increased risk of herpes zoster. Some authors20,32,33 have reported several instances of HZV infection, appearing with symptoms resembling an acute abdomen. The diagnosis is hard to pinpoint, and a vast array of examinations were required to pose it, sometimes even posthumously. The patients’ symptoms usually only appear with a sudden sharp pain in the abdomen, without any skin lesions or characteristics of neuropathic pain. These cases have open or microinvasive surgery and sometimes reveal a disseminated infection, engaging various abdominal organs.20,21,34 The diagnosis is suggested as the condition visceral zoster. The dissemination of the VZV infection to the abdominal organs is majorly found in immunocompromised patients following transplantation surgeries, an HIV infection, systemic treatment with corticosteroids, postsepticemic conditions, and others. Although similar in case to case, the symptoms of the infection represent with gastroenterological signs, such as bleeding ulcers in the gastrointestinal tract, acute abdomen with the typical syndromological evolution, and reactive hepatitis with no prior HCV infection or patient history pointing out environmental factors.21–23,35,36 In the aforementioned there were no apparent typical neurologic or skin signs.
Nephrologic and urologic involvement Nephrologic representations and complications have also been reported.37 At first, the clinical signs only manifest with direct imaging diagnostic and paraclinical signs of renal impairment or failure and no typical skin or neurologic condition to pinpoint. Some authors even suggest that the high overall incidence of HZV infection in the general
428 populace increases the morbidity rate of renally transplanted patients by as high as 30%.38 Urologic complications have also been reported, although usually these are secondary to a skin or neurologic representation of the VZV infection, the virus has started to be associated with the incidence of bladder cancer39 and acute urinary retention, with or without an apparent primary affect of the disease.40–42
HZ and immunocompromised patients The incidence of HZ complications is common in immunocompromised patients, and it is even higher in those with bone marrow transplantation. Diagnosis is difficult due to the fact that it can coexist together with a visceral dissemination. When this viral infection is discovered late, it is associated with high morbidity and mortality usually caused by acute respiratory distress, liver failure, pancreatitis, and others.43
Conclusions VZV infection has been recognized for more than a century as a skin or neurologic disease, but as science progresses, more basic evidence has emerged that this might not be the case. With more and more skin diseases being acknowledged as systemic ones, this viral infection is a more and more likely candidate for the same title.
References 1. Ropper AH, Samuels MA. Viral infections of the nervous system, chronic meningitis, and prion diseases. Adams and Victors’s Principles of Neurology. 9th ed. New York: McGraw-Hill, Inc; 2009. p. 711-745. 2. Jubelt B. Viral infections. In: Rowland LP, ed. Merritt’s Neurology, 11th ed. Philadelphia: Lippincot: Williams & Wilkins; 2005. p. 175-210. 3. Janninger CK, Eastern JS, Hospenthal DR, Moon JE. Herpes zoster. Emedicine. 2013; Medscape reference number 1132465. 4. James WD, Berger TG, Elston DM. Andrews' Diseases of the Skin: Clinical Dermatology. Philadelphia: Saunders/Elsevier. 2006. 5. Yawn BP, Wollan PC, Kurland MJ, St Sauver JL, Saddier P. Herpes zoster recurrences more frequent than previously reported. Mayo Clin Proc. 2011;86:88-93. 6. Harpaz R, Ortega-Sanchez IR, Seward JF. Advisory Committee on Immunization Practices (ACIP) Centers for Disease Control and Prevention (CDC) Prevention of herpes zoster: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2008;57(RR-5):1-30. 7. Kroth J, Tischer J, Samtleben W, et al. Isotopic response, Köbner phenomenon and Renbök phenomenon following herpes zoster. J Dermatol. 2011;38:1058-1061. 8. Fahlbusch M, Wesselmann U, Lehmann P. Herpes zoster after varicella-zoster vaccination. Hautarzt. 2013;64:107-109. 9. Gnann Jr JW, Whitley RJ. Herpes Zoster. N Engl J Med. 2002;347: 340-346.
I. Staikov et al. 10. Mick G, Gallais JL, Simon F, et al. Burden of herpes zoster and postherpetic neuralgia: incidence, proportion, and associated costs in the French population aged 50 or over. Rev Epidemiol Sante Publique. 2010:393-401. 11. Thyregod HG, Rowbotham MC, Peters M, et al. Natural history of pain following herpes zoster. Pain. 2007;128:148-156. 12. Niv D, Maltsman-Tseikhin A. Postherpetic neuralgia: the never-ending challenge. Pain Pract. 2005;5(4):327-340. 13. Hempenstall K, Nurmikko TJ, Johnson RW, et al. Analgesic therapy in postherpetic neuralgia: a quantitative systematic review. PLoS Med. 2005;2:e164. 14. Merchut MP, Review Gruener G. Segmental zoster paresis of limbs. Electromyogr Clin Neurophysiol. 1996;36:369-375. 15. Ropper AH, Samuels MA. Diseases of the cranial nerves. Adams and Victors’s Principles of Neurology, 9th ed. New York: McGraw-Hill, Inc; 2009. p. 1326-1340. 16. Sweeney CJD, Gilden H. Ramsay Hunt syndrome. J Neurol Neurosurg Psychiatry. 2001;71:149-154. 17. Iwasaki H, Toda N, Takahashi M, et al. Vestibular and cochlear neuritis in patients with Ramsay Hunt syndrome: a Gd-enhanced MRI study. Acta Otolaryngol. 2013;4:373-377. 18. Babtain FA, Bhatia HS, Assiri AH. Ramsay Hunt syndrome with multiple cranial neuropathies in a liver transplant recipient. Neurosciences (Riyadh). 2012;17:262-264. 19. Heymans F, Lacroix JS, Terzic A, Landis BN. Gustatory dysfunction after mandibular zoster. Neurol Sci. 2011;32:461-464. 20. Lin YY, Kao CH, Wang CH. Varicella zoster virus infection of the pharynx and larynx with multiple cranial neuropathies. Laryngoscope. 2011;121:1627-1630. 21. Chen PS, Lin YY, Huang BR. Pharyngolaryngeal zoster: a case report. Arch Otolaryngol Head Neck Surg. 2012;138:592-595. 22. Uscatequi T, Dorée C, Chamberlain IJ, Burton MJ. Antiviral therapy for Ramsay Hunt syndrome (herpes zoster oticus with facial palsy) in adults. Cochrane Database Syst Rev. 2008:CD006851. 23. Chang-Godinich A, Lee AG, Brazis PW, Liesegang TJ, Jones DB. Review. Complete ophthalmoplegia after zoster ophthalmicus. J Neuroophthalmol 17(4):262–265. 24. Czyz CN, Bacon TS, Petrie TP, Justice JD, Cahill KV. Isolated, complete paralytic mydriasis secondary to herpes zoster ophthalmicus. Pract Neurol. 2013;13:183-184. 25. Nithyanandam S, Joseph M, Stephen J. Ocular complications and loss of vision due to herpes zoster ophthalmicus in patients with HIV infection and a comparison with HIV-negative patients. Int J STD AIDS. 2013;24:106-109. 26. Hilt DC, Buchholz D, Drumholz A, Weiss H, Wolinsky JS. Herpes zoster ophthalmicus and delayed contralateral hemiparesis caused by cerebral angiitis: diagnosis and management approaches. Ann Neurol. 1983;14:543-553. 27. Melanson M, Chalk C, Georgevich L, et al. Varicella-zoster virus DNA in CSF and arteries in delayed contralateral hemiplegia. Evidence for viral invasion of cerebral arteries. Neurology. 1996;47:569-570. 28. Gilden D, Cohrs J, Mahalingam R, Nagel MA. Varicella zoster virus vasculopathies: diverse clinical manifestations, laboratory features, pathogenesis, and treatment. Lancet Neurol. 2009;8:731. 29. Mazur MH, Dolin R. Herpes zoster at the NIH: a 20 year experience. Am J Med. 1978;65:738-744. 30. Bangen KJ, Delano-Wood L, Wierenga CE, et al. Dementia following herpes zoster encephalitis. Clin Neuropsychol. 2010;24:1193-1203. 31. Long MD, Martin C, Sandler RS, Kappelman MD. Increased risk of herpes zoster among 108,604 patients with inflammatory bowel disease. Aliment Pharmacol Ther. 2013;37(4):420-429. 32. O’Loughlin CJ. Visceral varicella zoster after bone marrow transplantation. An obscure cause of an “acute abdomen. Dig Dis Sci. 1964;47:1962-1964. 33. Verdonck LF, Cornelissen JJ, Dekker AW, Rozenberg-Arska M. Acute abdominal pain as a presenting symptom of varicella-zoster virus infection in recipients of bone marrow transplants. Clin Infect Dis. 1993;16:190-191.
Herpes zoster 34. Yagi T, Karasuno T, Hasegawa T, et al. Acute abdomen without cutaneous signs of varicella zoster virus infection as a late complication of allogenic bone marrow transplantation: importance of empiric therapy with acyclovir. Bone Marrow Transplant. 2000;25:1003-1005. 35. Rogers SY, Irving W, Harris A, Russell NH. Visceral varicella zoster infection after bone marrow transplantation without skin involvement and the use of PCR for diagnosis. Bone Marrow Transplant. 1995: 15805-15807. 36. Krones E, Petritsch W, Valentin T, et al. Visceral dissemination of herpes zoster with multiple ulcers in the upper gastrointestinal tract of an apparently immunocompetent patient. Endoscopy. 2012;44 Suppl 2 UCTN:E302-3. doi: 10.1055/s-0032-1309926. [Epub 2012 Aug 29]. 37. Peritz DC, Duncan C, Kurek K, Perez-Atayde AR, Lehmann LE. Visceral varicella zoster virus (VZV) after allogeneic hematopoietic stem cell transplant (HSCT) in pediatric patients with chronic graft-versus-host disease (cGVHD). J Pediatr Hematol Oncol. 2008;30:931-934.
429 38. Jantsch J, Schmidt B, Bardutzky J, Bogdan C, Eckardt KU, Raff U. Lethal varicella-zoster virus reactivation without skin lesions following renal transplantation. Nephrol Dial Transplant. 2011;26:365-368. 39. Rommelaere M, Maréchal C, Yombi JC, Goffin E, Kanaan N. Disseminated varicella zoster virus infection in adult renal transplant recipients: outcome and risk factors. Transplant Proc. 2012;44: 2814-2817. 40. Panagiotakis GI, Papadogianni D, Chatziioannou MN, Lasithiotaki I, Delakas D, Spandidos DA. Association of human herpes, papilloma and polyoma virus families with bladder cancer. Tumour Biol. 2013;34:71-79. 41. Julia JJ, Cholhan HJ. Herpes zoster-associated acute urinary retention: a case report. Int Urogynecol J Pelvic Floor Dysfunct. 2007;18:103-104. 42. Chan JE, Kapoor A. Herpes zoster infection: a rare cause of acute urinary retention. Can J Urol. 2003;10:1912-1913. 43. Chen PH, Hsueh HF, Hong CZ. Herpes zoster-associated voiding dysfunction: a retrospective study and literature review. Arch Phys Med Rehabil. 2002;83:1624-1628.
Herpes zoster as a systemic disease Ivan Staikov, MD, PhD a,⁎, Neyko Neykov, MD a , Branka Marinovic, MD, PhD b , Jasna Lipozenčić, MD, PhD b , Nikolai Tsankov, MD, PhD, MSc a a
Departments of Neurology and Dermatology, Tokuda Hospital Sofia, Bulgaria Department of Dermatology, Medical Faculty, Zagreb, Croatia
b
Abstract Herpes zoster (shingles, zona) is a viral infection commonly affliccting the skin and the nervous system with an overall occurring rate of 3 to 5 cases per 1000 persons per year, with higher rates in middle or later life. With the advancement of medicine, more and more case reports have started to emerge showing different incidences of VZV, some new localizations, clinical presentations, and complications, which break the well-known fact that “VZV affects the skin and nervous system.” Skin lesions are the most important ones for the early and exact diagnosis of herpes zoster (HZ), due to its visibility and well-defined clinical picture of lesions. The most frequent condition following the acute herpes zoster eruption is postherapeutic neuralgia (PHN). There have been other reports of the disease with otorinolaryngologic complications and ophthalmologic ones, such as ophthalmoparesis/ plegia. There have also been reports of delayed contralateral hemiparesis/hemiplegia following the infection, as a manifestation of vaculitis due to a direct VZV invasion of the cerebral arteries. Encephalitis and destructive myelitis is similarly rare, but a serious complication. Some authors found that patients with inflammatory bowel disease are at a significantly increased risk for herpes zoster. As a gastroenterologic complication, there have been several instances of HZV infection with symptoms resembling an acute abdomen. The diagnosis is hard to pinpoint, and a vast array of examinations are required to identify it, sometimes even posthumously. Nephrologic representations and complications have also been reported. With more and more skin diseases being acknowledged as systemic ones, this viral infection is a more likely candidate for the same title. © 2014 Elsevier Inc. All rights reserved.
Introduction Herpes zoster (shingles, zona) is a viral infection commonly afflicting the skin and the nervous system with an overall occurring rate of 3 to 5 cases per 1000 persons per year, with higher rates in middle or later life.1 Especially at risk are immunocompromised patients, the incidence in whom is about 20 times higher. Some historical features of herpes zoster show that the neurologic implications of the segmental distribution of the eruption were recognized in 1831. The first description of ⁎ Corresponding author. Tel.: +359 88 49 33 001; fax: +359 2 403 44 03. E-mail address: [email protected] (I. Staikov). 0738-081X/$ – see front matter © 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clindermatol.2013.11.010
the inflammatory changes in the ganglia and related portions of the spinal nerves were made in 1862. In 1909, the concept that varicella and zoster are caused by the same agent was introduced.1 The virus that causes herpes zoster is the varicella zoster virus (VZV), the causative agent of varicella.2 VZV is a large, double strained DNA-containing virus, enclosed in a protein envelope that is similar in structure to the virus of herpes simplex. 1,2 The infection is usually clinically characterized by a skin eruption preceded and followed by pain in the distribution of the affected root ganglia. Primary VZV infection, which usually occurs in childhood, results in chickenpox (varicella), after which the virus becomes latent in the cranial nerve ganglia, dorsal root ganglia, and
Herpes zoster autonomic ganglia along the entire neuraxis. Later, as cellmediated immunity to VZV declines with age or is caused by immunosuppression (such as in organ-transplant recipients or in patients with cancer or HIV), VZV can reactivate and cause zoster. With the advancement of medicine, more and more case reports have started to emerge, showing different incidences of VZV, some new localizations, clinical presentations, and complications that break the well-known fact that “VZV affects the skin and nervous system.” Skin lesions are the most important ones for the early and exact diagnosis of herpes zoster (HZ) due to its visibility and well-defined clinical picture of lesions. Varicella zoster virus (VZV) moves down the nerve axon and causes skin lesions in the corresponding dermatome. Basically, skin lesions are determined as a dermatome eruption with pain, but clinically they are characterized with different phases3: • Preeruptive phase • Acute eruptive phase • Chronic phase
Preeruptive phase (preherpetic neuralgia) This prodromal period is characterized by sensory nerves phenomena, including paresthesias, pain, burning, or itching in the affected area. Usually, this period lasts 48 to 72 hours but could be extended to a week. Pain may resemble headache, brachial neuritis, cardiac pain, appendicitis, etc. Malaise, myalgia, headache, photophobia, and fever can be present along with the main neurologic symptoms.
Acute eruptive phase
425 localized in the same area as the skin lesions. Pain can be mild to severe often with a burning sensation and can last for a long period after the eruption has disappeared. Pain is described as stinging, tingling, aching, or burning. Pruritus is usually mild.
Clinical forms Disseminated herpes zoster The eruption in disseminated herpes zoster is localized within the borders of one or more primarily affected dermatomes.4 These extradermatomal vesicles occur a week after the onset of classic dermatomal herpes zoster. Disseminated herpes zoster occurs in approximately 2% of the zoster cases. This clinical form often develops in patients with depressed cellmediated immunity, which can be caused by various underlying clinical situations, including malignancies, radiation therapy, cancer chemotherapy, organ transplants, and long-term use of systemic corticosteroids.
Recurrent herpes zoster In one study, the frequency of herpes zoster (HZ) recurrence in a community population was higher than previously reported.5 In this study, 1669 patients with a medically documented episode of HZ were investigated. Out of a total number of patients, 95 of them had 105 recurrences. The Kaplan-Meier estimate of the recurrence rate at 8 years was 6.2%. With a maximum follow-up of 12 years, the time between HZ episodes in the same person varied from 96 days to 10 years.
Zoster sine herpete After the prodromal period, typical skin lesions appear involving one or a few neighboring dermatomes. At first, erythematous macular, papular or urticarial-like lesions become visible on the skin, but they quickly turn to vesicles. The typical vesicles are grouped in a herpetiform pattern on the erythematous skin. The size of the vesicles is between 1 to 2 mm, but some of them can become confluent. Skin lesions are always distributed unilaterally in a stripe or beltlike pattern. They do not cross the midline. In the beginning, the vesicles are clear, filled with serous fluid. After 3 to 5 days, the vesicles become hemorrhagic and thereafter dry out with brownish crusts. A new eruption may appear over a period of 3 to 4 days. These new lesions appear in the same area and have the same evolutionary polymorphism. Patients are infectious until the vesicles convert to crusts. Enlarged regional lymph nodes can be observed. The eruption heals within two to four weeks. Scarring is rare, usually only if there is a superinfection. The subjective symptoms are usually pain, pruritus, and/or hyperesthesia
Patients with this clinical form represent the entire symptom characteristic for herpes zoster except the typical eruption. Patients experience pain and weakness in a dermatomal distribution, but they have no skin signs, or in rare cases only erythematous macules or plaques with no vesicles.
Herpes zoster and immunodeficiency HZ rates of 29.4 to 51.5 per 1000 person/year have been reported among adults infected with the human immunodeficiency virus. In this form, due to severe immunodeficiency, the eruption often crosses the midline (Figure 1). In addition, higher rates have also been reported in persons with systemic lupus erythematosus, rheumatoid arthritis, granulomatosis with polyangiitis (Wegener), and inflammatory bowel disease.6
426
I. Staikov et al.
Herpes zoster and impetiginization of the lesions
Chronic phase (postherapeutic neuralgia)
This form is the result of a secondary bacterial infection at the site of the eruption (typically streptococcal or staphylococcal). Necrotizing fasciitis is a possible complication.
The most frequent condition following the acute herpes zoster eruption is postherapeutic neuralgia (PHN). PHN may affect cranial as well as peripheral nerves. The estimated incidence of PHN varies from country to country from 2.0 cases in 1000 people in the United States9 and 8.99/1000 in European countries, such as France.10 PHN is defined as pain at different time intervals after regression of the lesions of HZ in the affected dermatome. To confirm the diagnosis, there has to be daily pain that persists for 3 to 6 months after onset.11 PHN presents as chronic neuropathic pain in a dermatome with unpleasant sensations, such as “throbbing,” “shooting,” “stabbing,” etc. and a paroxysmal lancinating pain, which usually manifests every day and has a big impact on the patient’s quality of life.12 Current treatment involves opioids, tricyclic antidepressants, anticonvulsants, and lidocaine patches, which result only with partial pain relief, but the pain usually persists for months or years. The patient’s response to the treatment wildly varies, and the physician has to take into account and weigh out the possible various adverse effects of the medications for the pain relief and resulting quality of life.13 Any dermatome may be involved, but the most commonly involved are the thoracic dermatomes, particularly T5-T10, presenting in more than two-thirds of cases, followed by the craniocervical regions.1 Sometimes, a focal, asymmetric neurogenic weakness may occur in an extremity affected by cutaneous zoster. Such weakness is due to a lesion of the ventral nerve root, in close proximity to the inflammation in the initiating dorsal ganglion.14 Antiinflammatory treatment is usually administered together with antiviral treatment. Functional motor recovery appears in about 75% of cases within 1 to 2 years.
Wolf’s isotopic response (phenomenon) Inflammatory skin lesions following zoster infection can occur within the affected dermatome. Wolf's isotopic response may be explained as a special subtype of the Koebner phenomenon, in which one skin disease triggers another one.7
Herpes zoster after varicella-zoster vaccination 8 Varicella vaccine contains live attenuated VZV, which causes latent infection. The attenuated vaccine virus can reactivate the virus and cause herpes zoster. People who get vaccinated against varicella may develop herpes zoster later in life; however, their risk is lower than that of the people who were infected with the wild-type VZV. Vaccination also reduces the severity and duration of the disease, as well as its most common complication—postherapeutic neuralgia.
Neurologic and otorinolaryngological involvement
Fig. 1
Herpes zoster in HIV-positive patient.
A neurologic and otorinolaryngologic complication of VZV manifests as Ramsay Hunt syndrome (RHS). RHS is a peripheral facial nerve palsy, usually accompanied by a herpes zoster eruption in the external auditory canal, other parts of the cranial integument, and mucous membrane of the oropharynx, and affects the geniculate ganglion.15 Although similar to Bell’s palsy, its clinical symptoms are more heavily manifested, and there is a higher likelihood of multiple cranial nerve involvement.16 Compared with Bell’s palsy, patients with this syndrome often have more severe paralysis at the onset and are less likely to recover completely. Sometimes, due to the involvement of the vestibulocochlear nerve, RHS is accompanied by vertigo, tinnitus, and unilateral hearing loss,17 although there are reports of the involvement of other cranial nerves.18 Loss of taste over the anterior two-thirds of the tongue occurs in more than 50% of patients.2 There are several authors pinpointing VZV infection with RHS as a primarily
Herpes zoster otorinolaryngologic condition with a secondary dissemination toward the cranial nerves.19–21 Treatment involves usage of acyclovir and prednisone for a better outcome and prognosis.22
427 may cause asymmetric paraparesis, sensory lost, sphincter disturbances, and Brown-Sequard syndrome.1 Polyneuritis of the Guillain-Barre type has been also reported as a consequence of herpes zoster.2
Ophthalmologic involvement Gastrointestinal involvement There have been reports of ophthalmoparesis/plegia after herpes zoster ophthalmicus (HZO). Involvement of the trigeminal ganglion occurs in about 20% of patients and the first division—ophthalmic is the most frequently affected.2 Ophthalmoplegia as part of the sequela of HZO has typically been described as a late complication, often up to 2 months after the initial herpetic eruption.23 HZO involves not only the cranial nerve but also affects and impairs vision and causes damage to the eye bulbi and pupilae, as well as a pure ophthalmologic complication.24,25 Another complication of ophthalmic zoster is acute contralateral hemiplegia and ipsilateral hemisphere signs, such as aphasia, that can occur weeks or months later after HZO.2
Vasculopathy There have been reports of symptoms of delayed contralateral hemiparesis/hemiplegia following a VZV infection. This is a manifestation of vaculitis due to a direct VZV invasion of the cerebral arteries.26,27 This VZV vasculopathy affects both immunocompetent and immunocompromised patients, occurs after zoster or varicella, and can be either unifocal or multifocal. VZV vasculopathy among other conditions can cause ischemic stroke, potentiate a formation of an aneurysm, and sometimes indirectly cause subarachnoid and intraparenchimal cerebral hemorrhaging.28
Encephalitis Encephalitis is a rare but serious complication of herpes zoster. Although rare, it may occur in up to 5% of patients with HZ.29 A few studies have examined the brain changes and cognitive outcomes associated with herpes zoster encephalitis. They show variability in the brain regions affected, severity of neurologic damage, and cognitive deficit. Symptoms vary, the initial ones usually consist of headache, vomiting, fever, and altered sensory feel.30
Myelitis Destructive myelitis is similarly rare, but serious complication mainly of thoracic zoster. The signs of spinal cord involvement appear 15 to 21 days after the eruption and
Some authors have found that patients with inflammatory bowel disease are at a significantly increased risk for herpes zoster.31 They did a retrospective cohort and nested case– control study and analyzed more than 108,000 patients with inflammatory bowel disease and 430,000 matched controls. The overall annual incidence of herpes zoster per 100,000 person-years was 734 among inflammatory bowel disease patients, compared with 437 in noninflammatory bowel disease patients (incidence rate ratio = 1.68). This study gives evidences for an elevated risk for HZ in inflammatory bowel disease patients. According to the same paper, treatment with thiopurines, corticosteroids, and biologic antitumor necrosis factor–alpha (anti-TNF) agents was independently associated with an increased risk of herpes zoster. Some authors20,32,33 have reported several instances of HZV infection, appearing with symptoms resembling an acute abdomen. The diagnosis is hard to pinpoint, and a vast array of examinations were required to pose it, sometimes even posthumously. The patients’ symptoms usually only appear with a sudden sharp pain in the abdomen, without any skin lesions or characteristics of neuropathic pain. These cases have open or microinvasive surgery and sometimes reveal a disseminated infection, engaging various abdominal organs.20,21,34 The diagnosis is suggested as the condition visceral zoster. The dissemination of the VZV infection to the abdominal organs is majorly found in immunocompromised patients following transplantation surgeries, an HIV infection, systemic treatment with corticosteroids, postsepticemic conditions, and others. Although similar in case to case, the symptoms of the infection represent with gastroenterological signs, such as bleeding ulcers in the gastrointestinal tract, acute abdomen with the typical syndromological evolution, and reactive hepatitis with no prior HCV infection or patient history pointing out environmental factors.21–23,35,36 In the aforementioned there were no apparent typical neurologic or skin signs.
Nephrologic and urologic involvement Nephrologic representations and complications have also been reported.37 At first, the clinical signs only manifest with direct imaging diagnostic and paraclinical signs of renal impairment or failure and no typical skin or neurologic condition to pinpoint. Some authors even suggest that the high overall incidence of HZV infection in the general
428 populace increases the morbidity rate of renally transplanted patients by as high as 30%.38 Urologic complications have also been reported, although usually these are secondary to a skin or neurologic representation of the VZV infection, the virus has started to be associated with the incidence of bladder cancer39 and acute urinary retention, with or without an apparent primary affect of the disease.40–42
HZ and immunocompromised patients The incidence of HZ complications is common in immunocompromised patients, and it is even higher in those with bone marrow transplantation. Diagnosis is difficult due to the fact that it can coexist together with a visceral dissemination. When this viral infection is discovered late, it is associated with high morbidity and mortality usually caused by acute respiratory distress, liver failure, pancreatitis, and others.43
Conclusions VZV infection has been recognized for more than a century as a skin or neurologic disease, but as science progresses, more basic evidence has emerged that this might not be the case. With more and more skin diseases being acknowledged as systemic ones, this viral infection is a more and more likely candidate for the same title.
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