CLINICAL MANIFESTATIONS — The presenting clinical manifestations of herpes

zoster are usually characterized by rash and acute neuritis.

Rash — The rash of herpes zoster starts as erythematous papules, which quickly
evolve into grouped vesicles or bullae (picture 1). Within three to four days, these
vesicular lesions can become more pustular or occasionally hemorrhagic (picture
2 and picture 3). In immunocompetent hosts, the lesions crust by 7 to 10 days and are
no longer considered infectious. The development of new lesions more than a week
after presentation should raise concerns regarding possible underlying
immunodeficiency [1]. Scarring and hypo- or hyperpigmentation may persist months
to years after herpes zoster infection has resolved [2].

Zoster is generally limited to one dermatome in previously healthy hosts, but can
occasionally affect two or three neighboring dermatomes (figure 1 and figure 2). Some
patients have a few scattered vesicles located at some distance away from the
involved dermatome [1,3].

The thoracic and lumbar dermatomes are the most commonly involved sites of herpes
zoster (figure 1) [4]. A more serious infection, such as zoster keratitis or zoster
ophthalmicus, can result from involvement of the ophthalmic branch of the trigeminal
cranial nerve [2,5]. These can be sight-threatening infections. (See 'Complications in
immunocompetent patients' below.)

Fewer than 20 percent of patients have significant systemic symptoms, such as

headache, fever, malaise, or fatigue [1].

Acute neuritis — Pain is the most common symptom of zoster [6]; approximately 75
percent of patients have prodromal pain in the dermatome where the rash
subsequently appears [1]. Prodromal pain may be constant or intermittent and can
precede the rash by days to weeks [7]. Most patients describe a deep "burning",
"throbbing", or "stabbing" sensation [7]. Some individuals describe the pain only when
the involved area is touched, whereas others complain primarily of pruritus [8]. Pain
that is induced by simple mild brushing against the skin is referred to as "allodynia".

In the absence of vesicular rash, certain pain syndromes can be confused with other
etiologies, such as angina, cholecystitis, or renal colic, depending on the involved
dermatome [4,9]. In one study of 1669 patients with confirmed herpes zoster, 18
percent had acute neuritis for at least 30 days and the duration of pain increased with
age [4].

Atypical pain without rash — The concept that atypical pain syndromes may be
related to herpes zoster without rash, or "zoster sine herpete", has been raised. Some
clinical data showing serologic and PCR evidence of concurrent VZV reactivation have
supported this theory [10].

CLINICAL RECURRENCES — Recurrence of clinical zoster in the immunocompetent

host is uncommon (<5 percent) [11]. However, recurrences are more common in the
immunocompromised host [12,13]. In one study of HIV-infected patients (mean age
41 years), 282 episodes of herpes zoster were identified in 239 patients. Of these
episodes, 158 were new occurrences of zoster and 124 were recurrent zoster events
[12].

COMPLICATIONS IN IMMUNOCOMPETENT PATIENTS

Overview — The most common complication of herpes zoster is postherpetic

neuralgia. In one study, the percentage of patients with herpes zoster who developed
postherpetic neuralgia (defined as at least 90 days of documented pain) increased
from 5 percent in those younger than 60 years to 20 percent in those aged 80 years or
older [14]. A randomized placebo-controlled trial in more than 38,000 adults
demonstrated that zoster vaccine in the elderly reduces the incidence of PHN following
zoster by 67 percent [15]. (See "Prevention of varicella-zoster virus infection: Herpes
zoster".)

Other complications include ocular, neurologic, bacterial superinfection of the skin,

which can delay healing of the zoster lesions [2,5,16,17]. (See "Postherpetic
neuralgia".) Herpes zoster is not always limited to a spinal nerve distribution, but may
also extend centrally, which can result in meningeal inflammation and clinical
meningitis. Occasionally, VZV reactivation affects motor neurons in the spinal cord and
brainstem, resulting in motor neuropathies [2,3,5].

Incidence of complications — In a review of 859 patients with herpes zoster, 100

patients (12 percent) developed 123 complications within 60 days [5]. A single
complication occurred in 83 percent, two in 12 percent, and three or more in 5
percent. The risks of specific complications at 60 days were:

 Postherpetic neuralgia — 7.9 percent

 Bacterial skin infection — 2.3 percent
 Ocular complications including uveitis and keratitis — 1.6 percent (see "Uveitis:
Etiology; clinical manifestations; and diagnosis")
 Motor neuropathy — 0.9 percent
 Meningitis — 0.5 percent
 Herpes zoster oticus — 0.2 percent

Twenty-seven percent of patients with complications had ophthalmic (trigeminal)

zoster compared to the group of patients without complications in whom only 5 percent
had this dermatome involved. Advanced age was associated with postherpetic
neuralgia, bacterial superinfection of the skin, ocular complications, and motor
neuropathy. Patients with one or more complications had more frequent comorbidities
(eg, diabetes, cancer, HIV, transplant recipient).

Postherpetic neuralgia — Approximately 10 to 15 percent of all patients with herpes

zoster will develop postherpetic neuralgia (PHN) [18]; individuals older than 60 years
account for 50 percent of these cases [19]. PHN refers to pain persisting beyond four
months from the initial onset of the rash. Sensory symptoms can include pain,
numbness, dysesthesias, and allodynia (pain precipitated by movement) in the
affected dermatome. Immunosuppressed patients have a higher incidence of PHN.
This topic is discussed in detail elsewhere. (See "Postherpetic neuralgia".)

Herpes zoster ophthalmicus — Herpes zoster ophthalmicus (HZO), a serious sight-

threatening condition, has been linked to VZV reactivation within the trigeminal
ganglion [20,21]. Incidence rates of HZO complicating herpes zoster in various
population surveys have ranged from 8 to 56 percent [20,22]. The frontal branch
within the first division of the trigeminal nerve is most frequently involved, and 50 to
72 percent of patients experience direct ocular involvement [20].

The acute syndrome typically begins with a prodrome of headache, malaise, and fever;
unilateral pain or hypesthesia in the affected eye, forehead, and top of the head may
precede or follow the prodrome. With the onset of a vesicular eruption along the
trigeminal dermatome, hyperemic conjunctivitis, episcleritis, and lid droop can occur
(picture 4) [16,20,21]. Almost two-thirds of HZO patients develop corneal involvement
(keratitis) that results from a necrotic ganglionitis [20]; epithelial keratitis may feature
punctate or dendriform lesions. Iritis occurs in approximately 40 percent of patients
with herpes zoster ophthalmicus and can be associated with chronic vasculitis, atrophy,
and poorly reactive pupils [20].

Clinicians should also be aware that vesicular lesions on the nose are associated with a
high risk of herpes zoster ophthalmicus (Hutchinson's sign) [23]. Lesions in this area of
the face signify involvement of the nasociliary branch of the trigeminal nerve, which
also innervates the globe [24].

Early diagnosis is critical to prevent progressive corneal involvement and potential loss
of vision [25]. The standard approach to herpes zoster ophthalmicus is to initiate
antiviral therapy (acyclovir, valacyclovir, or famciclovir) to limit VZV replication and to
use adjunctive topical steroid drops to reduce the inflammatory response and control
immune keratitis and iritis [20,21,25,26]. Selected surgical procedures including
corneal transplant and lid repair are performed less often.

Acute retinal necrosis (ARN) — VZV has been implicated as the leading causative
pathogen of acute retinal necrosis (ARN) [27]; HSV has occasionally also been
identified as an etiologic agent [28-30] and has been described in patients with a
history of herpes encephalitis [31]. In a study evaluating samples of aqueous humor,
VZV DNA was detected in seven of the nine patients with necrotizing retinopathies of
suspected viral origin and in four of six patients with ARN [32]. (See "Retinal vasculitis
associated with systemic disorders and infections".)

ARN in the immunocompetent host — ARN has been reported in immunocompetent

hosts [32,33]. The clinical presentation features acute iridocyclitis, vitritis, necrotizing
retinitis, occlusive retinal vasculitis with rapid loss of vision, and eventual retinal
detachment [16,28,32,33]. Patients typically complain of blurred vision and pain in the
affected eye due to progressive necrotizing retinitis; the disease can subsequently
involve the other eye in 33 to 50 percent of patients [28]. The mechanism of bilateral
involvement is not clear, but one study found a diminished or absent VZV-specific
delayed hypersensitivity reaction in patients with ARN compared to patients with
herpes zoster involving only the skin [34]. Retinal detachment is a common
complication of ARN [27,35].

Intravenous acyclovir therapy for ARN usually affords clinical improvement in 48 to 72

hours [35] and can decrease the risk of contralateral eye involvement when
administered for more than three months [32]. One pharmacokinetic study evaluated
intravitreal drug concentrations in 10 patients with ARN after 24 hours of
oral valacyclovir and found substantial penetration, even in the uninflamed eye [36].
Some practitioners use oral antiviral agents for maintenance therapy, although there
does not appear to be a consensus on the need for long-term treatment [30]. There
are few data on the use of oral agents for the initial treatment of infection [37].

Systemic corticosteroid use may decrease the severity of ocular inflammation [27].

ARN in HIV-infected patients — In patients with advanced AIDS and ARN, the
following observations have been reported in the early era of potent ART [35]:

 Rapid progression was characteristic; only 4 of 20 involved eyes retained useful

vision at two-month follow-up, and 70 percent had no light perception at the
conclusion of the study.
 Eighty-two percent of patients had bilateral eye involvement; 70 percent
sustained retinal detachment.
 Seventy-three percent of patients had accompanying central nervous system
(CNS) disease presumably due to VZV virus.

There are few data in the past decade regarding the management of this syndrome,
which may be related to a decreased incidence of ARN in the era of potent HIV
therapy. In one 2007 case report, aggressive antiviral therapy with intravitreal
injections, initiation of ART, and serial sampling of vitreous for evidence of viral
replication led to a good clinical outcome in the setting of immune reconstitution [38].

Ramsay Hunt syndrome (Herpes zoster oticus) — The major otologic complication
of VZV reactivation is the Ramsay Hunt syndrome, which typically includes the triad of
ipsilateral facial paralysis, ear pain, and vesicles in the auditory canal and auricle
[39,40]. Taste perception, hearing (tinnitus, hyperacusis), and lacrimation are affected
in selected patients [40]. Ramsay Hunt syndrome is generally considered a polycranial
neuropathy with frequent involvement of cranial nerves V, IX, and X [39]. Vestibular
disturbances (vertigo) are also frequently reported. Ramsay Hunt syndrome has also
been reported in association with herpes simplex type 2 infection [41].

Ramsay Hunt syndrome has been linked to reactivation of latent VZV residing within
the geniculate ganglion [42] with subsequent spread of the inflammatory process to
involve the eighth cranial nerve. This results in auditory and vestibular disorders [43].
VZV DNA has been detected in 11 of 14 trigeminal ganglia (79 percent) and in 9 of 13
geniculate ganglia (69 percent) in adults but was not isolated from any newborn
ganglia specimens or from one adult seronegative for VZV [43]. These results indicate
that VZV becomes latent in the human geniculate ganglion after primary varicella
infection, and reactivation of VZV from the geniculate ganglion most likely precipitates
the Ramsay Hunt syndrome [43].

The facial paralysis seen in Ramsay Hunt syndrome is felt generally to be more severe
than Bell's palsy attributed to HSV, with increased rates of late neural denervation and
a decreased probability of complete recovery [44,45]. Antiviral therapy is usually
prescribed, although there are few data on this complication and management [46].

Other neurologic complications

Aseptic meningitis — Several studies conducted in patients with herpes zoster have
demonstrated that subclinical meningeal irritation, evidenced by a reactive
cerebrospinal fluid (CSF) pleocytosis, can occur in 40 to 50 percent of cases [47,48]. A
subset of immunocompetent patients with herpes zoster develops clinically evident
aseptic meningitis [49]; lumbar puncture typically confirms a brisk CSF pleocytosis and
an elevated protein concentration [50,51]. In a Finnish epidemiologic study of 144
patients with aseptic meningitis, an etiology was established in 66 percent of patients,
8 percent of whom had VZV infection [49].

Peripheral motor neuropathy — Segmental motor paresis develops in

approximately 3 percent of patients with zoster [47,52]. Peripheral motor weakness is
felt to result from spread of VZV from the dorsal root ganglia to the anterior root/horn;
the onset is typically coincident with the development of pain and cutaneous eruption
in a dermatomal distribution [47,52,53]. Muscle atrophy may result in the affected
region, but approximately 75 percent of patients experience gradual recovery of motor
strength [47].

Myelitis — Transverse myelitis occasionally complicates herpes zoster (usually

involving thoracic dermatomes (figure 1)) within days to weeks following the initial
onset of the vesicular rash [47,54]. Myelitis is a more frequent complication in HIV-
infected patients and involves direct spread of VZV from the dorsal root ganglia
centrally into the spinal cord [55,56]. Several reports describing zoster myelitis in HIV-
infected patients in the absence of any rash have documented VZV DNA within spinal
cord specimens at autopsy [55].

Encephalitis — Zoster-associated encephalitis typically presents with delirium within

days following the vesicular eruption but may occur prior to the onset of rash or follow
an episode of zoster by more than six months [47,57]. While apparently normal hosts
may develop VZV encephalitis, the majority of cases have been reported in
immunosuppressed patients, such as HIV-infected individuals [16,47,57-59]. Major
risk factors identified for the development of zoster encephalitis include cranial or
cervical dermatomal involvement, two or more prior episodes of zoster, disseminated
herpes zoster, and impaired cell-mediated immunity [47,58].

AIDS patients may develop a leukoencephalitis associated with CNS white matter
demyelination and cerebral vasculopathy due to ongoing VZV replication within the
brain parenchyma [47,60]. Response to acyclovir therapy in AIDS patients has been
variable due to the frequent emergence of acyclovir-resistant VZV strains during long-
term exposure to the drug [61-63]. CSF PCR assays, in conjunction with MRI brain
imaging studies, have facilitated more rapid diagnosis of VZV-induced encephalitis in
selected patients [64,65].

Guillain-Barré syndrome — Data from a Taiwan health registry was extracted to

determine if there was an increased risk of Guillain-Barré Syndrome (GBS) among
those with a history of herpes zoster within the prior two months of presentation [66].
Of 315,595 patients with a history of herpes zoster, 0.03 percent developed GBS.
Although GBS was a relatively rare event, the risk of developing this syndrome was
significantly higher among patients with a recent history of zoster compared with
controls, who were matched by age and sex. (See "Clinical features and diagnosis of
Guillain-Barré syndrome in adults".)

Stroke syndromes — VZV infection can produce stroke syndromes secondary to

infection of cerebral arteries. In a series of 30 patients with VZV vasculopathy,
diagnosed by either VZV-specific antibodies or VZV DNA in the CSF, rash occurred in
19 (63 percent) and CSF pleocytosis in 20 (67 percent) [67]. Angiography
demonstrated the involvement of both large and small arteries in approximately half of
the patients. (See "Stroke caused by varicella zoster virus".)

The pathogenesis of stroke following an episode of dermatomal zoster has been linked
to direct viral invasion of cerebral arteries with VZV by extension along the intracranial
branches of the trigeminal nerves resulting in an inflammatory process within the
internal carotid artery or its branches on the side ipsilateral to the rash [16,68].

Granulomatous vasculitis of the large and small arteries, with VZV antigens detectable
in the smooth muscle cells of the media, has been confirmed in several autopsy studies
[69]. These pathologic findings have suggested that the syndrome results from direct
VZV invasion of the arterial surface via spread along the intracranial branches of the
trigeminal nerve [47,69]. The mortality rate is at least 20 percent, and survivors have
severe neurologic deficits [47].

HZO has rarely been complicated by contralateral thrombotic stroke syndrome in some
patients [47,69,70]. (See "Stroke caused by varicella zoster virus".) This catastrophic
syndrome typically occurs within several weeks to a few months after the zoster
eruption [47] and is heralded by the abrupt onset of severe headache and rapid
evolution to contralateral motor weakness. Cerebral angiography demonstrates
multifocal occlusion of the proximal branches of the anterior and middle cerebral
arteries [71].

Bacterial infections — Immunocompetent and immunocompromised adults with

localized herpes zoster are at risk for developing soft tissue infection with bacterial
pathogens, such as staphylococcus and streptococcus [72,73]. In addition to antiviral
therapy, antibiotics targeting these bacterial pathogens is indicated when this
complication occurs.

COMPLICATIONS IN IMMUNOCOMPROMISED HOSTS — Immunocompromised

hosts, including both HIV-infected patients and transplant recipients, remain at
substantial risk for severe VZV-related complications [16,47,55,56,74-77].
Immunocompromised patients such as transplant recipients [78,79] and HIV-infected
individuals with advanced disease [78,80] are at increased risk for developing
complicated herpes zoster infections including cutaneous dissemination and visceral
end organ involvement. Cutaneous dissemination often presents with multiple vesicular
skin lesions in a generalized distribution affecting a number of distinct dermatomes
that cross the midline. Visceral organ involvement due to herpes zoster may present in
a fulminant and rapidly evolving syndrome with pneumonia, hepatitis, or encephalitis
and may occasionally develop in the absence of coincident rash [79].

Disseminated VZV has been documented in both solid organ transplant recipients and
in patients with hematologic malignancies undergoing chemotherapy [75,81,82].
Cutaneous dissemination is often accompanied by visceral involvement [82,83].
Visceral dissemination in the immunosuppressed transplant patient is a life-threatening
emergency [84]. In transplant patients, reactivation of VZV typically occurs later than
CMV or HSV [85]. Cutaneous lesions may be delayed, or atypical with hemorrhage
[84].

VZV pneumonitis in transplant recipients has been associated with a high mortality
despite prompt diagnosis and the empiric institution of antiviral therapy [86].

Bone marrow transplant recipients — VZV dissemination remains the most

frequent late infection of allogeneic bone marrow transplant (BMT) recipients [81,82];
concurrent graft versus host disease (GVHD) has been identified as a major risk factor
for dissemination [82]. (See "Overview of infections following hematopoietic cell
transplantation".) Infection with reactivated VZV occurs in 35 percent of allogeneic
BMT recipients at one year; almost 50 percent of these patients will develop
disseminated VZV [87]. Visceral VZV dissemination can be accompanied by
pneumonitis, hepatitis, pancreatitis, and/or meningoencephalitis [76,77].

Selected BMT recipients have presented with acute, severe abdominal pain as the
initial manifestation of visceral reactivated VZV in the absence of antecedent cutaneous
rash, hepatitis, or pneumonitis [81,88]. The appearance of a zoster rash as long as 10
to 14 days after abdominal pain begins has frequently delayed prompt diagnosis and
resulted in a poor outcome despite the institution of appropriate antiviral therapy.

HIV-infected patients — HIV-infected patients are at increased risk of developing

herpes zoster than the general population and are at increased risk of neurologic and
ophthalmologic complications [16].

The incidence and clinical spectrum of herpes zoster was evaluated in an urban clinic of
HIV-infected patients; 52 episodes of zoster occurred in 45 patients during 1614
person-years of follow-up (incidence, 3.2 episodes per 100 person-years) [74]. In this
study conducted in the pre-HAART era, low CD4 count was associated with zoster-
related complications, such as retinal necrosis and aseptic meningitis.

One retrospective study evaluated VZV infections before and after the introduction of
potent ART [89]. The incidence of HZ in the pre-HAART era (17 per 100 person years)
was significantly higher than that in the post-HAART era (5 per 100 person-years).
Furthermore, in both eras, the incidence of HZ was higher in the first six months after
initiating ART than between 6 and 12 months. Another retrospective study with a case-
control design determined that 18 percent of patients who had herpes zoster
developed PHN [12].

Reactivation of herpes zoster has also been reported as part of the immune
reconstitution inflammatory syndrome [90-92]. This topic is discussed in detail
elsewhere. (See "Immune reconstitution inflammatory syndrome".