Shingles

The earliest symptoms of shingles, which include headache, fever, and malaise, are nonspecific, and may result in an incorrect diagnosis. These symptoms are commonly followed by sensations of burning pain, itching, hyperesthesia (oversensitivity), or paresthesia ("pins and needles": tingling, pricking, or numbness). Pain can be mild to severe in the affected dermatome, with sensations that are often described as stinging, tingling, aching, numbing or throbbing, and can be interspersed with quick stabs of agonizing pain. Shingles in children is often painless, but people are more likely to get shingles as they age, and the disease tends to be more severe. In most cases, after one to two days, and sometimes as long as three weeks, the initial phase is followed by the appearance of the characteristic skin rash. The pain and rash most commonly occur on the torso but can appear on the face, eyes, or other parts of the body. At first, the rash appears similar to hives; however, unlike hives, shingles causes skin changes limited to a dermatome, typically resulting in a stripe or belt-like pattern on one side of the body and not crossing the midline. Later, the rash becomes vesicular, forming small blisters filled with a serous exudate, as the fever and general malaise continue. The painful vesicles eventually become cloudy or darkened as they fill with blood and crust over within seven to ten days; usually, the crusts fall off, and the skin heals, but sometimes, after severe blistering, scarring, and discolored skin remain. Face Shingles may have additional symptoms, depending on the dermatome involved. The trigeminal nerve is the most commonly involved nerve, of which the ophthalmic division is the most commonly involved branch. When the virus is reactivated in this nerve branch, it is termed zoster ophthalmicus. The skin of the forehead, upper eyelid, and orbit of the eye may be involved. Zoster ophthalmicus occurs in approximately 10–25% of cases. In some people, symptoms may include conjunctivitis, keratitis, uveitis, and optic nerve palsies, which can sometimes cause chronic ocular inflammation, vision loss, and debilitating pain. Shingles oticus, also known as Ramsay Hunt syndrome type II, involves the ear. It is thought to result from the virus spreading from the facial nerve to the vestibulocochlear nerve. Symptoms include hearing loss and vertigo (rotational dizziness). Sometimes this leads to unnecessary dental treatment. Post-herpetic neuralgia is uncommonly associated with shingles in the mouth. respectively), making the condition potentially lethal. ==Pathophysiology==

of varicella zoster virus. Approximately 150,000× magnification. The virus diameter is 150–200 nm. , break open (3), crust over (4), and finally disappear. Postherpetic neuralgia can sometimes occur due to nerve damage (5).|thumb The causative agent for shingles is the varicella zoster virus (VZV)—a double-stranded DNA virus related to the herpes simplex virus. Most individuals are infected with this virus as children, which causes an episode of chickenpox. The immune system eventually eliminates the virus from most locations, but it remains dormant (or latent) in the ganglia adjacent to the spinal cord (called the dorsal root ganglion) or the trigeminal ganglion in the base of the skull. Shingles occurs only in people who have been previously infected with VZV; although it can occur at any age, approximately half of the cases in the United States occur in those aged 50 years or older. Shingles can recur. It is extremely rare for a person to have more than three recurrences. Due to difficulties in studying VZV reactivation directly in humans (leading to reliance on small-animal models), its latency is less well understood than that of the herpes simplex virus. Although VZV has been detected in autopsies of nervous tissue, there are no methods to find dormant virus in the ganglia of living people. Unless the immune system is compromised, it suppresses viral reactivation and prevents shingles outbreaks. Why this suppression sometimes fails is poorly understood, but shingles is more likely to occur in people whose immune systems are impaired due to aging, immunosuppressive therapy, psychological stress, or other factors. Upon reactivation, the virus replicates in neuronal cell bodies, and virions are shed from the cells and carried down the axons to the area of skin innervated by that ganglion. In the skin, the virus causes local inflammation and blistering. The short- and long-term pain caused by shingles outbreaks originates from inflammation of affected nerves due to the widespread growth of the virus in those areas. As with chickenpox and other alpha-herpesvirus infections, direct contact with an active rash can spread the virus to a person who lacks immunity. This newly infected individual may then develop chickenpox, but will not immediately develop shingles. ==Diagnosis==

If the rash has appeared, identifying this disease (making a differential diagnosis) requires only a visual examination, since very few diseases produce a rash in a dermatomal pattern. However, herpes simplex virus (HSV) can occasionally produce a rash in such a pattern (zosteriform herpes simplex). When the rash is absent (early or late in the disease, or in the case of ), shingles can be difficult to diagnose. Apart from the rash, most symptoms can also occur in other conditions. Laboratory tests are available to diagnose shingles. The most popular test detects VZV-specific IgM antibody in blood; this appears only during chickenpox or shingles and not while the virus is dormant. In larger laboratories, lymph collected from a blister is tested by polymerase chain reaction (PCR) for VZV DNA, or examined with an electron microscope for virus particles. Molecular biology tests based on in vitro nucleic acid amplification (PCR tests) are currently considered the most reliable. Nested PCR test has high sensitivity, but is susceptible to contamination leading to false positive results. The latest real-time PCR tests are rapid, easy to perform, and as sensitive as nested PCR, and have a lower risk of contamination. They also have more sensitivity than viral cultures. Differential diagnosis Shingles can be confused with herpes simplex, dermatitis herpetiformis and impetigo, and skin reactions caused by contact dermatitis, candidiasis, certain drugs and insect bites. == Prevention ==

Shingles risk can be reduced in children by the varicella vaccine if the vaccine is administered before the individual gets chickenpox. If primary infection has already occurred, there are shingles vaccines that reduce the risk of developing shingles or developing severe shingles if the disease occurs. Vaccine efficacy was maintained through four years of follow-up. As of 2016, it had been studied only in people with an intact immune system. By August 2017, just under half of eligible 70–78 year olds had been vaccinated. About 3% of those eligible by age have conditions that suppress their immune system, and should not receive Zostavax. In the US, it is recommended that healthy adults 50 years and older receive two doses of Shingrix, two to six months apart. ==Treatment==

Treatment aims to limit the severity and duration of pain, shorten the duration of a shingles episode, and reduce complications. Symptomatic treatment is often needed for the complication of postherpetic neuralgia. However, a study on untreated shingles shows that, once the rash has cleared, postherpetic neuralgia is very rare in people under 50 and wears off in time; in older people, the pain wore off more slowly, but even in people over 70, 85% were free from pain a year after their shingles outbreak. Analgesics People with mild to moderate pain can be treated with over-the-counter pain medications. Topical lotions containing calamine can be used on the rash or blisters and may be soothing. Occasionally, severe pain may require an opioid medication, such as morphine. Once the lesions have crusted over, capsaicin cream (Zostrix) can be used. Topical lidocaine and nerve blocks may also reduce pain. Administering gabapentin along with antivirals may offer relief of postherpetic neuralgia. however, they do not prevent postherpetic neuralgia. Of these drugs, aciclovir has been the standard treatment, but the newer drugs valaciclovir and famciclovir demonstrate similar or superior efficacy and good safety and tolerability. Steroids Corticosteroids do not appear to decrease the risk of long-term pain. Zoster ophthalmicus , from top: exudative erythema, scabs, blister, eyelid swelling Treatment for zoster ophthalmicus is similar to standard treatment for shingles at other sites. A trial comparing aciclovir with its prodrug, valaciclovir, demonstrated similar efficacies in treating this form of the disease. ==Prognosis ==

The rash and pain usually subside within three to five weeks, but about one in five people develop a painful condition called postherpetic neuralgia, which is often difficult to manage. In some people, shingles can reactivate, presenting as zoster sine herpete: pain radiating along the path of a single spinal nerve (a dermatomal distribution), but without an accompanying rash. This condition may involve complications that affect several levels of the nervous system and cause many cranial neuropathies, polyneuritis, myelitis, or aseptic meningitis. Other serious effects that may occur in some cases include partial facial paralysis (usually temporary), ear damage, or encephalitis. There is a slightly increased risk of developing cancer after a shingles episode. However, the mechanism is unclear, and mortality from cancer did not appear to increase as a direct result of the presence of the virus. Instead, the increased risk may result from the immune suppression that allows the reactivation of the virus. Although shingles typically resolves within 3–5 weeks, certain complications may arise: • Secondary bacterial infection. • Eye involvement: trigeminal nerve involvement (as seen in herpes ophthalmicus) should be treated early and aggressively, as it may lead to blindness. Involvement of the tip of the nose in the zoster rash is a strong predictor of herpes ophthalmicus. • Postherpetic neuralgia, a condition of chronic pain following shingles. ==Epidemiology==

Varicella zoster virus (VZV) has a high level of infectivity and has a worldwide prevalence. Shingles is a reactivation of latent VZV infection: zoster can only occur in someone who has previously had chickenpox (varicella). Shingles has no relationship to season and does not occur in epidemics. There is, however, a strong relationship with increasing age. This relationship with age has been demonstrated in many countries, and is attributed to the fact that cellular immunity declines as people grow older. Another important risk factor is immunosuppression. Other risk factors include psychological stress. According to a study in North Carolina, "black subjects were significantly less likely to develop zoster than were white subjects." It is unclear whether the risk is different by sex. Other potential risk factors include mechanical trauma and exposure to immunotoxins. but a 2010 study found no such link. However, upon closer inspection, the two studies that showed no increase in shingles incidence were conducted among populations where varicella vaccination was not as yet widespread in the community. A later study by Patel et al. concluded that since the introduction of the chickenpox vaccine, hospitalization costs for complications of shingles increased by more than $700 million annually for those over age 60. Another study by Yih et al. reported that as varicella vaccine coverage in children increased, the incidence of varicella decreased, and the occurrence of shingles among adults increased by 90%. The results of a further study by Yawn et al. showed a 28% increase in shingles incidence from 1996 to 2001. It is likely that incidence rate will change in the future, due to the aging of the population, changes in therapy for malignant and autoimmune diseases, and changes in chickenpox vaccination rates; a wide adoption of zoster vaccination could dramatically reduce the incidence rate. A study of 1994 California data found hospitalization rates of 2.1 per 100,000 person-years, rising to 9.3 per 100,000 person-years for ages 60 and up. An earlier Connecticut study found a higher hospitalization rate; the difference may be due to the prevalence of HIV in the earlier study, or to the introduction of antivirals in California before 1994. ==History==

Shingles has a long recorded history, although historical accounts fail to distinguish the blistering caused by VZV and those caused by smallpox, In the late 18th century William Heberden established a way to differentiate shingles and smallpox, and in the late 19th century, shingles was differentiated from erysipelas. In 1831 Richard Bright hypothesized that the disease arose from the dorsal root ganglion, and an 1861 paper by Felix von Bärensprung confirmed this. Recognition that chickenpox and shingles were caused by the same virus came at the beginning of the 20th century. Physicians began to report that cases of shingles were often followed by chickenpox in younger people who lived with the person with shingles. The idea of an association between the two diseases gained strength when it was shown that lymph from a person with shingles could induce chickenpox in young volunteers. This was finally proved by the first isolation of the virus in cell cultures, by the Nobel laureate Thomas Huckle Weller, in 1953. Some sources also attribute the first isolation of the herpes zoster virus to Evelyn Nicol. Until the 1940s, the disease was considered benign, and serious complications were thought to be very rare. However, by 1942, it was recognized that shingles was a more serious disease in adults than in children and that it increased in frequency with advancing age. Further studies during the 1950s on immunosuppressed individuals showed that the disease was not as benign as once thought, and the search for various therapeutic and preventive measures began. By the mid-1960s, several studies identified the gradual reduction in cellular immunity in old age, observing that in a cohort of 1,000 people who lived to the age of 85, approximately 500 (i.e., 50%) would have at least one attack of shingles, and 10 (i.e., 1%) would have at least two attacks. In historical shingles studies, shingles incidence generally increased with age. However, in his 1965 paper, Hope-Simpson suggested that the "peculiar age distribution of zoster may in part reflect the frequency with which the different age groups encounter cases of varicella and because of the ensuing boost to their antibody protection have their attacks of zoster postponed". Also, the study by Terada et al. indicated that pediatricians reflected incidence rates from 1/2 to 1/8 that of the general population their age. ==Etymology==

The family name of all the herpesviruses derives from the Greek word , from ("to creep"), referring to the latent, recurring infections typical of this group of viruses. Zoster comes from Greek , meaning "belt" or "girdle", after the characteristic belt-like dermatomal rash. The common name for the disease, shingles, derives from the Latin , a variant of Latin , meaning "girdle". ==Research==

Until the mid-1990s, infectious complications of the central nervous system (CNS) caused by VZV reactivation were regarded as rare. The presence of rash, as well as specific neurological symptoms, was required to diagnose a CNS infection caused by VZV. Since 2000, PCR testing has become more widely used, and the number of diagnosed cases of CNS infection has increased. Classic textbook descriptions state that VZV reactivation in the CNS is restricted to immunocompromised individuals and the elderly; however, studies have found that most participants are immunocompetent and younger than 60 years old. Historically, vesicular rash was considered a characteristic finding, but studies have found that rash is only present in 45% of cases. MRI and CT scans are usually normal in cases of VZV reactivation in the CNS. CSF pleocytosis, previously thought to be a strong indicator of VZV encephalitis, was absent in half of a group of people diagnosed with VZV encephalitis by PCR. Diagnosis of complications of varicella-zoster, particularly in cases where the disease reactivates after years or decades of latency, is difficult. A rash (shingles) can be present or absent. Symptoms vary, and there is a significant overlap in symptoms with herpes simplex symptoms. Notwithstanding these limitations, the use of PCR has resulted in an advance in the state of the art in our understanding of herpesviruses, including VZV, during the 1990s and 2000s. For example, in the past, clinicians believed that encephalitis was caused by herpes simplex and that people always died or developed serious long-term functional problems. People were diagnosed at autopsy or by brain biopsy. Brain biopsy is not undertaken lightly: it is reserved only for serious cases that cannot be diagnosed by less invasive methods. For this reason, knowledge of these herpes virus conditions was limited to severe cases. DNA techniques have made it possible to diagnose "mild" cases, caused by VZV or HSV, in which the symptoms include fever, headache, and altered mental status. Mortality rates in treated people are decreasing. == References ==