The incidence of herpes zoster appears to be increasing [5,12-14]. As an example, in a population-based cohort study of 8017 patients with herpes zoster in Minnesota, the incidence rate was 0.76 per 1000 person-years from 1945 to 1949, and increased to 3.15 per 1000 person-years from 2000 to 2007 [13]. In a large study of veterans, the annual incidence rates significantly increased from 3.1 episodes per 1000 veterans in 2000 to 5.2 in 2007 [12]. The reason for this increase is unclear. 

In the early 1900s, many viewed "shingles" as a viral illness that was acquired from person-to-person contact, similar to "chickenpox." The hypothesis that zoster was secondary to reactivation of latent varicella-zoster virus (VZV) infection was first proposed in 1965 [60]. The precise mechanisms involved in the establishment of viral latency following primary VZV infection have been an ongoing focus of investigation.

Cell-free virus, which is present only in skin vesicles, infects nerve endings in skin and migrates along sensory axons to establish latency in neurons within the regional ganglia [63,67-69]. VZV proteins accumulate preferentially in the cytoplasm of neurons during latency, but migrate to the nucleus during productive infection [70]. Once reactivation occurs, virus can spread to other cells within the ganglion to involve multiple sensory neurons and thereby establish infection of the skin [2].

A guinea pig model has been developed to examine viral latency and reactivation in vitro [67]. In this model, infection of sensory neurons with cell-associated virus leads to lytic infection; in contrast, cell-free virus establishes latency [67]. During latency, the virus only expresses a limited number of viral proteins, such as immediate early protein 63 (IE63) [71]. Immunity to this protein may play a role in maintaining the virus in a latent state [72].

VZV-specific cell-mediated immune responses play a critical role in controlling VZV latency and limiting the potential for reactivation [2,50,73,74]. A more detailed discussion of the importance of cell-mediated immunity, and how it relates to zoster vaccination, is presented elsewhere.

Following varicella-zoster virus (VZV) reactivation, the dorsal spinal ganglion typically exhibits intense inflammation, accompanied by hemorrhagic necrosis of nerve cells [60]. The ganglion undergoes eventual neuronal loss with subsequent fibrosis of afferent nerve fibers, particularly type C nociceptors [75].

The dermatomal distribution of the vesicular rash of herpes zoster corresponds to the sensory fields of many infected neurons within a specific ganglion [2]. Mapping of the involved sensory areas, related to each ganglion, was first conducted in 1900 in detailed autopsy studies of persons who had recent zoster [76]. 

Understanding the pathophysiology involved in reflex syncope is essential to understanding its clinical manifestations and prevention strategies. Both neural (arterial and cardiac baroreceptor, including carotid sinus reflexes) and endogenous chemical pathways are thought to be involved (figure 1)Â [4].

The most frequent mechanism for reflex syncope is a mixed cardioinhibitory response combining cardioinhibitory and vasodepressor features, although an individual patient may have syncopal events characterized principally by vasodepressor, cardioinhibitory, or mixed responses. Typically the episodes can vary in their presentation for any individual such that asystole may occur at one time and hypotension at another. 

Alterations in autonomic activation are responsible for reflex syncope. Vasovagal syncope may be caused by autonomic cardioinhibitory and/or vasodilator responses. Three types of responses are seen [5]:

—Cardioinhibitory response “ The cardioinhibitory response results from increased parasympathetic activation and may be manifested by any or all of the following: sinus bradycardia, PR interval prolongation, advanced atrioventricular block, or asystole.

—Vasodepressor response “ The vasodepressor response is due to inhibition of (decreased) sympathetic activity and can lead to symptomatic hypotension even in the absence of severe bradycardia. In one report, for example, the final trigger for symptomatic hypotension appeared to be the abrupt disappearance of muscle sympathetic nerve activity [6]. Reduced cardiopulmonary baroreceptor sensitivity may be a contributing factor [7].

—Mixed response “ The mixed response contains components of both the cardioinhibitory response and the vasodepressor response.

Autonomic dysfunction contributes to reflex syncope, particularly in those whose presentation does not include the usual premonitory symptoms, and is often associated with cardiovascular or neurologic disorders, which may include orthostatic or postprandial hypotension [1,2]. Autonomic dysfunction is also thought to play a role in some vasovagal syncope, but vasovagal syncope also occurs without apparent autonomic dysfunction. 

Reflexes initiated in various arterial and cardiac baroreceptors and carotid sinus reflexes may be involved (in the past, the term Bezold-Jarisch reflex has been used, but it is now best abandoned as it does not fully express the complex pathophysiology) [4]. Patients may have increased muscle sympathetic nerve activity at rest and a blunted response to orthostatic stress [9].

—Baroreceptor reflexes “ Receptors in the atria, great veins, and left ventricle exist whose activation results in reflex bradycardia and vasodilation. Activation of these mechanoreceptors (including those in the left ventricle and stretch receptors in the great vessels) with pressure or volume changes (as may occur with sympathetic stimulation) activate afferent C fibers to the midbrain; such stimulation may result in activation of vagal afferents and then vagal efferents.

—Carotid sinus reflex “ Blood pressure and heart rate are normally controlled in part by input from baroreceptors located within the carotid sinus and aortic arch. An increase in blood pressure or pressure applied to the carotid sinus enhances the baroreceptor firing rate and activates vagal activity, thereby slowing the heart rate and reducing the blood pressure.

Vasovagal syncope (also known as the "common faint") refers to a variety of clinical scenarios in which a neural reflex results in usually self-limited systemic hypotension characterized by bradycardia and/or peripheral vasodilation [11]. It is the most common cause of syncope (approximately 35 to 70 percent of cases depending on the age group being evaluated), particularly in patients without apparent cardiovascular or neurologic disease [12-18]. However, vasovagal syncope remains the most common cause of syncope even among patients with heart disease and should be considered as a potential cause in such patients after more worrisome causes (table 2) have been excluded [15]. 

Vasovagal syncope is a common cause of syncope in athletes. However, other potential causes of syncope should be considered, particularly if the syncope occurs during exertion (ie, during "full flight" not during the post exercise cooling down period). Athletes with syncope during physical activity should be evaluated for underlying structural heart disease, which, if present, increases potential risk of sudden death.

Situational syncope refers to syncope associated with specific scenarios. Some situations (eg, post-micturition, post-tussive, etc) appear to trigger a neural reflex; others (eg, straining, squatting) may cause syncope via additional mechanisms unrelated to neural reflexes. Avoidance of trigger situations is the first step in prevention of recurrences.