VIRUSES (EXCEPT RETROVIRUSES) AND VIRAL DISEASES
was a central scotoma in the visual field of the right eye,
and ophthalmoscopy showed multiple lesions of the retinal
pigment epithelium consistent with APMPPE. The patient
also had a significant peripheral eosinophilia. Over the next
several months, the eosinophilia gradually decreased, visual
acuity in the right eye slowly improved to 20/25, and the
lesions of the retinal pigment epithelium became hyperpig-
mented. A second case of recombinant HBV vaccine-in-
duced APMPPE was described by Brézin et al. (153) in a
30-year-old man with visual loss in the right eye 2 weeks
after a booster injection of vaccine. Visual acuity was 20/20
OD and 20/200 OS. Four weeks after immunization, fundus
examination revealed multiple pale lesions within the tem-
poral arcades. One month later, the fundus appearance and
fluorescein angiograms showed pigment scarring in both
eyes. Blood cell counts were normal. At 4 months, vision
had improved to 20/30 OS, although there was a residual
paracentral scotoma.
It seems clear that both plasma-derived and recombinant
HBV vaccines produce a variety of systemic, neurologic,
and visual side effects in rare patients. Nevertheless, the risk
of HBV infection, particularly in certain populations, is so
high, the potential complications of HBV infection are so
significant, and the efficacy of HBV vaccines is so great that
the use of HBV vaccine clearly is warranted in appropriate
high-risk persons.
HERPESVIRIDAE
The members of the Herpesviridae family are large, DNA-
containing, enveloped viruses. The name ‘‘herpes’’ is de-
rived from a Greek word for the spreading skin eruption that
is caused by some of these viruses and from the French word
herper, meaning ‘‘to creep.’’ About 80 herpesviruses infect
animals, and 8 regularly infect humans (154):
1. Herpes simplex virus type 1 (human herpesvirus type 1,
HSV-1)
2. Herpes simplex virus type 2 (human herpesvirus type 2,
HSV-2)
3. Varicella-zoster virus (human herpesvirus type 3, VZV)
4. Epstein-Barr virus (human herpesvirus type 4, EBV)
5. Cytomegalovirus (human herpesvirus type 5, CMV)
6. Human herpesvirus type 6 (HHV-6, B-lymphotropic
virus)
7. Human herpesvirus 7 (HHV-7)
8. Human herpesvirus type 8 (HHV-8, Kaposi’s sarcoma-
associated herpesvirus)
A ninth herpesvirus, simian herpes B virus (B virus, Her-
pesvirus simiae), usually infects monkeys, although it occa-
sionally infects humans and produces significant neurologic
disease.
Pathogenesis of Herpesviruses
Herpesviruses induce disease in three ways: by direct de-
struction of tissue, by inducing immunopathologic re-
sponses, and by facilitating neoplastic transformation. Mu-
cocutaneous manifestations of HSV, VZV, and simian
3129
herpes B virus infections are the direct consequences of tis-
sue destruction by the replicating virus (154). Visceral infec-
tions with these viruses and with CMV, including pneumoni-
tis, hepatitis, retinitis, and encephalitis, also reflect virus-
induced cellular destruction. On the other hand, other com-
plications of herpesvirus infections, such as erythema multi-
forme, hemolytic anemia, and thrombocytopenia, are pri-
marily immune-mediated. The neurologic complications that
occur in patients with chickenpox and herpes zoster, includ-
ing encephalitis, transverse myelitis, and cranial neuropa-
thies, typically arise as the cutaneous component of the VZV
infection is resolving, and these phenomena are also thought
to be immune-mediated, even though the virus is occasion-
ally detected in affected CNS tissues and may, in fact, con-
tribute directly to neurologic dysfunction in some settings.
Similarly, most of the clinical manifestations of infection
with EBV, including both hematologic and neurologic com-
plications, are immune-mediated. Except in the setting of
severe congenital or acquired cellular immune deficiency
disorders, only a small fraction of the cells that infiltrate the
lymph nodes, liver, and spleen in patients with primary EBV
infection are virus-infected B lymphocytes. In addition,
chronic infection with EBV is associated with the develop-
ment of certain B-cell lymphomas and nasopharyngeal carci-
noma. The precise role played by this virus in the develop-
ment of these malignancies is unclear, but it is assumed that
the virus somehow confers growth advantages on certain
cells, thereby increasing opportunities for spontaneous chro-
mosomal translocations or other potentially transforming
events to occur, and allowing tumor cells to escape immune
surveillance (154). In the sections that follow, we discuss
the specific herpesviruses and the clinical syndromes they
produce, emphasizing conditions that are of neuro-ophthal-
mologic significance.
Herpes Simplex Virus
Two types of herpes simplex viruses can infect humans:
HSV-1 and HSV-2 (155). These viruses can be differentiated
by their unique biochemical and biologic characteristics and
also by their tendency to produce separate clinical syn-
dromes. In particular, their DNA is different with respect to
its base composition, and although they share certain glyco-
protein antigens, they differ with respect to others. Thus,
serologic differentiation between HSV-1 and HSV-2 can be
readily made by detection of type-specific antibodies and by
DNA analysis.
Epidemiology and Pathogenesis
Herpes simplex viruses are present throughout the world
in both developed and developing countries. Humans seem
to be their only natural reservoir. Direct contact, with trans-
mission through infected secretions, is the principal mode
of spread. HSV-1 is transmitted primarily by contact with
oral secretions, whereas HSV-2 is transmitted by contact
with genital secretions (156). Thus, most lesions caused by
HSV-1 are on the face, and most lesions caused by HSV-2
are in the genital region. Nevertheless, changing sexual
mores and increasing oral–genital contact have resulted in
3130 CLINICAL NEURO-OPHTHALMOLOGY
Figure 57.4. Replication of herpesviruses. The initial event is fusion of
the virion with the plasma membrane of the host cell at a specific receptor
site, at which time the viral envelope is removed (1). The nucleocapsid with
its surrounding tegument enters the cell cytoplasm (2) and is transported to
the cell nucleus, during which time the tegument releases proteins that
halt cellular protein synthesis, regulate their own synthesis, and eventually
stimulate the synthesis of other viral proteins that are used in the replication
of the viral genome. The tegument is then released from the nucleocapsid.
Once the nucleocapsid arrives at the nucleus of the host cell, the viral DNA
is released. The capsid remains at the nuclear pore, and only the DNA is
released into the nucleus (3). Once within the nucleus of the host cell, the
viral DNA induces synthesis of further viral proteins and enzymes that, in
turn, permit synthesis of more viral nucleic acid and formation of new
virions (4). Newly synthesized viral DNA is subsequently packaged within
newly formed capsids (5). The nucleocapsids then leave the nucleus, be-
come enveloped, and are released from the cell by exocytosis (6). (From
Liesegang TJ. Biology and molecular aspects of herpes simplex and vari-
cella-zoster virus infections. Ophthalmology 1992;99⬊781–799.)
an increased incidence of genital HSV-1 and oral HSV-2
infections. Transmission can occur from both symptomatic
and asymptomatic infected persons, although virus titers
tend to be higher in persons with active disease, and trans-
mission from contact with such persons probably is more
likely to occur than it is from contact with someone who
is asymptomatic (154). Most persons become infected with
HSV-1 during childhood, whereas the major period for infec-
tion with HSV-2 is after puberty and correlates with increas-
ing sexual activity. Patients with AIDS are at increased risk
of developing HSV infections (157), probably because of
co-infection and also because of synergy between HSV and
HIV-1.
Recurrent infection occurs frequently after both HSV-1
and HSV-2 primary infections. Most recurrences are caused
by endogenous reactivation of latent virus, rather than by
exogenous reinfection, and they occur despite circulating
anti-HSV antibodies.
Replication of HSV (Fig. 57.4) begins as soon as the virus
comes in contact with a mucosal surface or abraded skin.
Initial replication occurs locally in parabasal and intermedi-
ate epithelial cells, resulting in ballooning and lysis of the
infected cells and local inflammation that includes the for-
mation of multinucleated giant cells. This series of events
produces the characteristic lesion of superficial HSV infec-
tion, a thin-walled vesicle on a base of inflammatory mono-
nuclear, polymorphonuclear, and multinucleated giant cells.
Lymphatics and regional lymph nodes draining the site of
primary infection become infected themselves. Further repli-
cation of the virus may then result in viremia and dissemina-
tion to various organs, including the liver, lungs, and CNS,
depending on the status of the host’s immune system (155).
During local replication of HSV, viral nucleocapsids are
transported by neurons to the dorsal root ganglia (158). Once
within the ganglia, the virus again replicates and then be-
comes dormant, to be reactivated at a later date under the
proper conditions and stimuli. Upon reactivation, HSV, or
at least viral genetic information, is transported peripherally
by the same peripheral sensory nerves that initially trans-
ported the virus to the ganglia. These nerves seem to be
unique in that production of fully infectious virus does not
cause cell lysis and death, although it is suggested that only
early viral products are actually produced within the neuron
and that the final viral replicative assembly occurs within
epithelial cells to which the virus is transported (155). Once
HSV is transported to cutaneous sites, further spread is local
from cell to cell, with the extent of spread controlled by
humoral and cellular immune mechanisms.
Latent virus can be demonstrated in humans in several
different ganglia, including the trigeminal, sacral, and vagal
ganglia (155). In addition, latent virus may remain in the
human cornea after an attack of herpetic keratitis (159,160).
Subsequent reactivation of latent virus (Fig. 57.5) depends
not only on the production of certain regulatory genes within
the virus but also on the integrity of the anterior root and
Figure 57.5. Mechanism of reactivation of herpesviruses. Diagrammatic
representation of three theories of reactivation. The ‘‘ganglion trigger’’
theory postulates that a stimulus to the ganglion or the sensory nerve causes
release of a virus that travels down the nerve and produces clinical disease
in a localized area that corresponds to the sensory nerve. The ‘‘skin trigger’’
theory postulates that the virus is frequently shed from the sensory nerve
and establishes microfoci of disease at the peripheral site. Stimulation of
the skin produces a favorable condition for replication of virus. The ‘‘gan-
glion and skin trigger’’ theory postulates that virus can persist in the periph-
eral tissues, that stimulation of the ganglion or nerve increases viral shed-
ding, and that stimulation of the skin produces favorable conditions for
viral replication. (From Liesegang TJ. Biology and molecular aspects of
herpes simplex and varicella-zoster virus infections. Ophthalmology 1992;
99⬊781–799.)
 VIRUSES (EXCEPT RETROVIRUSES) AND VIRAL DISEASES
peripheral nerve pathways, although all areas supplied by
a latently infected nerve are not equally affected. In fact,
recurrences usually develop in the vicinity of the primary
infection.
Clinical Manifestations
PRIMARY INFECTIONS
Primary HSV-1 infection is frequently asymptomatic, but
it may present as gingivostomatitis and pharyngitis. Most
affected patients are children under 5 years of age, but older
children and adults may also present in a similar fashion.
Incubation periods range from 2–12 days and are followed
by fever and sore throat associated with pharyngeal edema
and erythema. Shortly after the onset of these manifestations,
small vesicles develop on the pharyngeal and oral mucosa.
The vesicles rapidly ulcerate and increase in number, extend-
ing to the soft palate, buccal mucosa, tongue, and floor of
the mouth. The disease usually runs its course in 10–14 days
with no sequelae, although cervical adenopathy may persist
for several weeks.
Primary genital HSV infection occurs most often in ado-
lescents and young adults, with 70–95% of cases being
caused by HSV-2 (155,160a). The incubation period ranges
from 2–5 days. Primary HSV genital infection in both men
and women may be associated with fever, malaise, anorexia,
and tender bilateral inguinal adenopathy, and extragenital
lesions develop in up to 30% of patients during the course
of the primary infection. The central and peripheral nervous
systems are affected in many of these cases.
HSV-1 and HSV-2 infection cause some cases of Mollar-
et’s meningitis (161–163). This condition, first described in
1944, is characterized by a recurrent aseptic meningitis that
initially is associated with a neutrophilic pleocytosis and
later with a lymphocytic pleocytosis.
Aseptic meningitis, usually caused by HSV-2 but occa-
sionally by HSV-1, develops in 10–36% of patients with
a primary genital HSV infection (155,164–168). It occurs
primarily in sexually active women and homosexual men in
the second to fourth decades of life. The symptoms include
fever, headache, and stiff neck. Papilledema occurs in some
patients, as do cranial neuropathies. The CSF typically
shows a lymphocytic pleocytosis with a moderately in-
creased concentration of protein and a normal or low glucose
concentration. HSV may be isolated from the CSF, although
an assay for HSV DNA using PCR is a more sensitive diag-
nostic test. HSV meningitis is almost always self-limited,
and recovery usually is complete without any neurologic
sequelae, although, as noted earlier, some patients develop
recurrent lymphocytic (Mollaret’s) meningitis (161,169,
170). It is not clear if treatment with antiviral drugs speeds
recovery.
Meningitis caused by HSV occasionally occurs in patients
without any genital or other mucocutaneous lesions
(171,172). The correct diagnosis often is delayed in such
cases.
A sacral radiculomyelitis may accompany primary HSV
genital infection, and this may cause neuralgias, obstipation,
and urinary retention. Patients in whom this phenomenon
3131
occurs may demonstrate loss of anal tone, a diminished bul-
bocavernosus reflex, and evidence of lower motor neuron
disease by cystometrography (173–175). Occasionally, radi-
culomyelitis occurs in the absence of preceding or concomi-
tant herpetic skin lesions (174).
HSV-1 is a major etiologic agent in Bell’s palsy (176).
Viral genomes of HSV-1, VZV, and EBV were analyzed in
clinical samples of facial nerve endoneurial fluid and poste-
rior auricular muscle, using PCR followed by hybridization
with Southern blot analysis. HSV-1 genomes were detected
in 79% of patients with Bell’s palsy but in no patients with
Ramsay-Hunt syndrome or in other controls.
Sudden bilateral sensorineural hearing loss can result from
HSV-1 infection (177). MR imaging in such cases usually
shows enhancement of the intracanalicular portions of the
seventh and eighth cranial nerve complexes.
The eye may be a site of primary HSV infection (178).
Most infections occur in adolescents and young adults, are
caused by HSV-1, and are characterized by a unilateral fol-
licular conjunctivitis associated with regional lymphadenop-
athy (179–181). Occasionally, the infection is bilateral
(182). Blepharitis with vesicles on the eyelid margin may
occur, and affected patients may develop photophobia, ex-
cessive lacrimation, chemosis of the conjunctiva, and edema
of the eyelids. In addition, patients occasionally develop ves-
icles on the eyelids, well away from the eyelid margin.
Rarely, the skin lesions and conjunctivitis caused by HSV
appear similar to those seen in patients with herpes zoster
ophthalmicus. This condition is called zosteriform herpes
simplex (183). Some patients develop keratitis characterized
by typical dendritic defects in the corneal epithelium (den-
dritic keratitis) that are almost pathognomonic of the disease
(184,185) (Fig. 57.6); others develop nonspecific punctate
defects in the corneal epithelium. Both types of keratitis may
be associated with swelling of the corneal stroma. Bilateral
progressive corneal stromal opacification may occur in chil-
dren (186). When ocular inflammation is limited to the con-
junctiva, the disease usually runs its course over 2–3 weeks,
but the disease often persists longer when the cornea is af-
fected.
Some cases of isolated acute or chronic uveitis without
evidence of keratitis are caused by primary HSV infection
(187). In most of these cases, the uveitis is of the anterior
variety (Fig. 57.7). HSV may also be the etiologic agent in
some cases of the Posner-Schlossman syndrome (glaucoma-
tocyclitic crisis) (188), the iridocorneal endothelial syn-
drome (189), and dacryoadenitis (190).
HSV retinitis and chorioretinitis can occur in isolation
without evidence of either disseminated HSV infection or
HSV encephalitis in children and adults who are immuno-
suppressed from drugs or disease (191). Patients with lym-
phoreticular malignancies and AIDS seem to be at particular
risk for this complication. The histopathologic findings in
such cases are identical with those seen in infants with con-
genital or neonatal HSV infection and include retinal necro-
sis, infiltration of the retina with chronic inflammatory cells,
typical intranuclear inclusions in retinal cells, and retinal
phlebitis with occlusion of retinal veins (191). A marked
inflammatory reaction may be present in the vitreous and
3132 CLINICAL NEURO-OPHTHALMOLOGY
Figure 57.6. Dendritic keratitis caused by primary infection with herpes simplex in a 60-year-old man. A, Slit-lamp appearance
shows typical superficial opacification of the cornea from epithelial defects that have a dendritic pattern. B, Fluorescein staining
of the cornea highlights the dendrite.
Figure 57.7. Iridocyclitis with iris atrophy from primary infection with
herpes simplex virus in a 38-year-old man. A, Slit-lamp appearance of the
right eye shows anterior uveitis. Note keratic precipitates on the inferior
cornea. B, Several weeks after the onset of symptoms, the right iris shows
marked atrophy and depigmentation. (From Chang TS, Brewer LV, Hooper
PL. Primary herpes simplex iridocyclitis with iris atrophy. Arch Ophthalmol
1993;111⬊25–26.)
in the choroid underlying the retinal inflammation (178).
Nonnecrotizing herpetic retinopathies may masquerade as
severe posterior uveitis with clinical presentations such as
a birdshot-like chorioretinopathy (192)
Acute retinal necrosis (ARN) syndrome is a diffuse uveitis
characterized by a peripheral necrotizing retinitis and retinal
vasculitis associated in many cases with anterior chamber
inflammation, vitritis, papillitis, or a combination of these
manifestations (193). Herpesviruses are the causative agents
in many cases of ARN. Although most cases of ARN are
caused by VZV, immunocytologic staining of pathologic
specimens from some patients with ARN identifies HSV-
1 or HSV-2 as the responsible agent (193–203,203a). An
inflammatory optic neuropathy may be the presenting fea-
ture of ARN caused by HSV (200), and some cases of pro-
gressive outer retinal necrosis (PORN), a variant of ARN,
may also be due to HSV infection (204). HSV-1-induced
ARN may present with a severe inflammatory orbitopathy,
proptosis, and optic nerve involvement (203).
ARN may occur in isolation, or it may occur after, or
concurrent with, primary HSV infection, including herpes
simplex keratitis, meningitis, and encephalitis (205–211)
(Fig. 57.8). Margolis et al. (212) reported a variant of the
ARN syndrome characterized by an arcuate neuroretinitis in
which evaluation of serial serum antibody titers suggested
HSV-2 as the causative agent (Fig. 57.9). How the virus
gains access to the retina in an otherwise healthy person is
unclear, but this might occur by either vascular dissemina-
tion or reactivation of a latent focus of previously unrecog-
nized infection (213).
RECURRENT INFECTIONS
Recurrent extragenital mucocutaneous HSV infections
initially cause prodromal symptoms, such as pain, burning,
 VIRUSES (EXCEPT RETROVIRUSES) AND VIRAL DISEASES 3133

Figure 57.8. Acute retinal necrosis syndrome caused by primary infection with herpes simplex virus. The patient was a 22-
year-old man who developed decreased vision in the left eye. Visual acuity was 20/20 OD and no light perception OS. There
was a significant inflammatory reaction in the anterior chamber of the left eye, and there were a few scattered vitreous cells
in the eye. A, Appearance of the posterior pole of the left ocular fundus. The view is hazy because of the intraocular inflammation.
Nevertheless, the left optic disc is swollen, and there is irregular whitening of the macula. B, Appearance of the inferotemporal
region of the left ocular fundus. Note extensive perivenous hemorrhage with marked retinal whitening. C, Fluorescein angiogram
(arteriovenous phase) of the inferotemporal region of the left ocular fundus shows occlusion of peripheral retinal arteries and
veins. D, B-scan ultrasonogram of the left eye shows an exudative retinal detachment. A diagnosis of acute retinal necrosis
was made, and a retinal biopsy was performed that showed necrosis associated with intracellular inclusions consistent with
herpesvirus infection. Culture of the vitreous yielded herpes simplex type 1 virus, and serologic testing was consistent with a
recent infection with HSV-1. (From Duker JS, Nielsen JC, Eagle RC Jr, et al. Rapidly progressive acute retinal necrosis
secondary to herpes simplex virus type 1. Ophthalmology 1990;97⬊1638–1643.)

tingling, or itching, that usually last less than 6 hours. Vesi-
cles then appear and are associated with severe pain. The
vesicles progress to ulceration with crusting within 48 hours,
following which healing occurs over 8–10 days (Fig. 57.10).
Interestingly, systemic complaints usually do not accompany
these recurrent infections, although local adenopathy may
occur.
Recurrent extragenital HSV infections are rarely associ-
ated with neurologic complications, but Steven and Nath-
wani (214) reported two such cases. Both patients were teen-
agers being treated for acute meningococcal meningitis with
benzylpenicillin and dexamethasone when they developed
evidence of infections caused by HSV. One of the patients,
a 17-year-old boy, developed severe stomatitis that was
treated with topical acyclovir ointment. Fourteen days later,
he developed a left peripheral facial nerve paresis, decreased
hearing on the left, and intermittent pain behind the left ear.
The second patient, a 16-year-old girl, developed a cold sore
on the lip and then experienced acute right-sided hearing
loss associated with a left peripheral facial paresis. One week
later, she reported pain in the left ear. Both patients were
treated with systemic corticosteroids and improved over sev-
3134 CLINICAL NEURO-OPHTHALMOLOGY

Figure 57.9. Acute retinal necrosis (ARN) syndrome presenting with papillitis and arcuate retinitis in a 48-year-old woman
with serologic evidence of infection with herpes simplex virus type 2 (HSV-2). The patient reported decreased vision in the
right eye and had visual acuity of 20/400 OD, and there was a right-sided relative afferent pupillary defect. A, Visual field of the
right eye, as determined by tangent (Bjerrum) screen examination, shows a dense inferior arcuate scotoma. B, Ophthalmoscopic
appearance of right fundus. The right optic disc is mildly swollen and hyperemic, and there is an arcuate area of retinitis
somewhat resembling a patch of myelinated nerve fibers that extends from the superior aspect of the optic disc to the horizontal
raphe. C, Fluorescein angiogram (mid arteriovenous phase) shows blocked choroidal fluorescence in the region of the retinitis.
D, Fluorescein angiogram (late arteriovenous phase) shows late hyperfluorescence of the right optic disc and the region of
retinitis. (From Margolis T, Irvine AR, Hoyt WF, et al. Acute retinal necrosis syndrome presenting with papillitis and arcuate
neuroretinitis. Ophthalmology 1988;95⬊937–940.)

eral weeks. The neurologic complications in both patients
were believed to have been caused by reactivation of latent
HSV related to the meningococcal meningitis, its treatment,
or both.
Recurrent genital herpes infections in both men and
women usually are less severe and associated with fewer
and less severe systemic manifestations than are primary
genital infections caused by HSV (160a). Recurrences tend
to be more severe in women than in men, and lesions in
both sexes tend to heal slowly over 6–10 days. Recurrent
genital HSV infection is occasionally associated with the
development of aseptic meningitis identical with that occur-
ring in patients with primary genital HSV infection
(165,167). The meningitis usually is caused by HSV-2 (215),
but HSV-1 is rarely the cause (216). Active genital lesions
are absent at the time the meningitis develops in about 70%
of patients, but such patients almost always give a history
of having such lesions at some time in the past. As with the
aseptic meningitis that accompanies primary genital HSV
infection, the aseptic meningitis of recurrent HSV infection
usually produces headache, fever, and photophobia. Papille-
dema caused by increased intracranial pressure develops in
 VIRUSES (EXCEPT RETROVIRUSES) AND VIRAL DISEASES
Figure 57.10. Recurrent herpes simplex infection on the face. The infec-
tion began 48 hours after the patient underwent removal of a meningioma
from the left cerebellopontine angle. Note resemblance to the appearance
of herpes zoster, except for the involvement of the upper lip. The exanthem
resolved completely within a week without leaving any residual scarring.
some cases, and cranial neuropathies are not uncommon.
Most patients recover completely with supportive care, but
some have persistent neurologic deficits.
After primary infection, HSV-2 establishes a latent infec-
tion, generally in the sacral ganglia, from which virus can
be recovered at autopsy. It seems most likely that axoplasmic
spread of the virus from these ganglia is responsible for both
the primary meningitis that occurs with recurrent HSV-2
infection and the recurrent HSV-2 meningitis that can occur
in the absence of evidence of recurrent genital infection
(217).
Recurrent ocular infection with HSV may occur as kerati-
tis, blepharitis, or keratoconjunctivitis (218). Recurrent kera-
titis is unilateral in 88–98% of cases, and it takes one of
two forms: dendritic or stromal. The dendritic form of recur-
rent HSV keratitis is identical to that which occurs as a pri-
mary manifestation of the disease. It is characterized by the
appearance of a linear branching (dendritic) epithelial defect
that has elevated edges and stains with fluorescein dye. The
stromal form consists of a growing opacification of the cen-
tral cornea that usually is unassociated with significant epi-
thelial disease (Fig. 57.11). Both forms of recurrent herpetic
keratitis are often accompanied by complete loss of corneal
sensation on the affected side, and the combination of a
keratitis associated with acquired ipsilateral loss of corneal
sensation is almost diagnostic of herpetic keratitis. Most le-
sions heal with time, but the stromal form of recurrent HSV
3135
Figure 57.11. Severe stromal keratitis caused by recurrent infection with
(reactivation of latent?) herpes simplex virus. A, In a 46-year-old man. Note
extensive ingrowth of vessels from limbus into the cornea associated with
central corneal opacification. B, In a 58-year-old woman. Note the promi-
nent peripheral corneal pannus and extensive stromal opacification. (A,
From Shimomura Y, Mori Y, Inoue Y, et al. Herpes simplex virus latency
in human cornea. Jpn J Ophthalmol 1993;37⬊318–324. B, From Brik D,
Dunkel E, Pavan-Langston D. Persistence of viral particles despite topical
and systemic antiviral therapy: report of two cases and review of the litera-
ture. Arch Ophthalmol 1993;111⬊522–527.)
keratitis is particularly recalcitrant and may eventually cause
permanent corneal scarring, neovascularization, calcifica-
tion, and, in some cases, thinning with spontaneous perfora-
tion. HSV particles at various stages of maturity, including
completely enveloped virions, may be seen in basal cells
and keratocytes of the cornea (219). Patients in whom such
complications occur usually have permanent visual loss.
Some authors believe that recurrent herpetic keratitis is
caused by reactivation of latent virus in corneal epithelial
cells rather than in the ipsilateral trigeminal ganglion (220).
A number of studies on human corneal buttons, obtained
during the quiescent stage of herpes simplex keratopathy,
have reported the detection of viral DNA using PCR and
immunohistology (221–223). The presence of viral DNA in
corneas, long after the active keratitis episode has subsided,
3136 CLINICAL NEURO-OPHTHALMOLOGY
has led to the hypothesis of extraneuronal herpetic latency
in the cornea (221,222). HSV within a donor cornea may
cause endothelial destruction in organ culture and both pri-
mary graft failure and ulcerative keratitis after corneal trans-
plantation (221,224–227).
CONGENITAL AND NEONATAL INFECTION
Primary HSV infection of the fetus during embryogenesis
may cause spontaneous abortion or premature labor, ending
in death of the fetus (228). Congenitally infected neonates
may have jaundice, hepatosplenomegaly, a bleeding
diathesis, and skin vesicles at birth (229). Ophthalmologic
disturbances are common in these infants and include micro-
phthalmia, corneal scarring with and without neovasculari-
zation, cataracts, and acute retinitis or chorioretinitis similar
to that seen in infants with congenital toxoplasmosis
(178,230,231). Persistent severe retinitis or chorioretinitis
may be associated with panuveitis, retinal detachment, and
optic atrophy, resulting in permanent visual loss (232). Mi-
croscopic examination in acute cases shows extensive retinal
necrosis associated with a retinal infiltrate consisting of
chronic inflammatory cells. Intranuclear inclusions may be
seen in some cells, and an inflammatory reaction may be
present in both the vitreous and the choroid underlying the
affected retina (228,233). The inflammation subsides over
time, leaving extensive chorioretinal scarring. Optic atrophy
is present in some cases, as are disturbances of ocular motil-
ity. In the absence of typical skin lesions, the ocular lesions
caused by congenital HSV infection may be difficult to dis-
tinguish from those caused by other DNA viruses.
Neonatal HSV infection, in contrast to congenital infec-
tion, occurs several days to weeks after birth and tends to
mimic neonatal sepsis (234). Vesicles may or may not be
present; in the latter setting, unilateral or bilateral conjuncti-
vitis may be the first abnormality that is observed, often
occurring in association with a mild keratitis. The eye is the
only site of HSV infection in rare cases (235).
Congenital and neonatal HSV infection may produce sig-
nificant neurologic symptoms and signs that can occur in
isolation, as a severe encephalitis, or as a component of a
multiorgan disseminated infection (236,237). There usually
are associated skin vesicles. The manifestations of the en-
cephalitis include seizures, cranial neuropathies, lethargy,
irritability, tremors, poor feeding, temperature instability,
pyramidal tract signs, cortical blindness, and, in severe cases,
coma and death (234). These manifestations usually become
evident during the second and third weeks after birth. Infants
in whom CNS manifestations occur invariably have pleo-
cytosis with increased protein and normal glucose concentra-
tions in the CSF. When the infection is acquired during early
gestation, it produces a spectrum of pathologic changes that
range from severe encephaloclastic lesions to minor focal
calcifications (228). Acute neonatal infections are associated
with diffuse brain involvement without localization to the
frontal and temporal lobes, as is typical of infection in older
children and adults (discussed later). The neuropathologic
changes in such patients include microglial nodules with
affected cells containing intranuclear inclusions. A predilec-
tion for endothelial cells results in thrombosis and hemor-
rhagic infarction.
Although some children with localized disease recover
without sequelae, many, particularly those with dissemi-
nated disease, develop severe complications, such as micro-
cephaly, encephalomalacia, and intracranial calcification,
that may preclude survival or, in survivors, normal function-
ing (234). Visual acuity may be disturbed not only by pri-
mary ocular defects but also by optic atrophy or cortical
blindness. Neonates and infants with HSV-2 infection have
a higher mortality and a worse neurologic prognosis than do
children with HSV-1 infection (238).
ENCEPHALITIS
Although encephalitis is a rare complication of HSV in-
fection, HSV is one of the most common causes of viral
encephalitis in the United States and many other countries,
particularly in children (239,240). It is estimated to occur in
about 1 in 250,000 to 1 in 500,000 persons per year around
the world (241,242). HSV encephalitis is almost always
caused by HSV-1, although rare cases of encephalitis caused
by HSV-2 occur in patients of all ages (243,244).
HSV encephalitis can occur in patients of any age, of
either sex, of any socioeconomic status, and at any time
of the year (240,245,246). Most patients who develop this
disorder have been previously healthy; however, HSV en-
cephalitis may occur with greater frequency in patients after
bone marrow transplantation than in the general population
(247) and also in persons with AIDS, in whom the disease
is particularly severe (243,248). HSV encephalitis also can
occur after skull fracture (249), during pregnancy (250), and
after intracranial surgery (251,252), probably from reactiva-
tion of latent intracranial virus.
About one third of cases of HSV encephalitis are the result
of primary infection (241). Most of these cases occur in
patients less than 18 years of age. The remaining cases occur
in patients with pre-existing antibodies against HSV and thus
are thought to be caused by spontaneous reactivation of the
virus (253). About 10% of these patients have a history of
recurrent HSV infection, however. Balfour and Lockman
(254) described a 17-month-old girl who developed HSV
encephalitis 15 months after an episode of HSV keratitis.
Both the keratitis and encephalitis occurred on the same side,
supporting the concept of reactivation and spread of latent
virus from the ipsilateral trigeminal nerve or ganglion to the
brain.
Most patients with HSV encephalitis have typical but non-
specific manifestations, including altered consciousness,
fever, and headaches (240,241,246,255–257). Multiple find-
ings are not always present at the onset of the disease, how-
ever. Young et al. (258) described a patient in whom impair-
ment of short-term memory was the sole presenting
symptom of HSV encephalitis. Transient global amnesia was
the first manifestation in a patient described by Kimura et
al. (259), and isolated psychosis was the first manifestation
in a patient described by Sage et al. (260). Seizures may
occur, particularly in children, but also in adults (261).
Hemiparesis may occur in patients with HSV encephalitis,
 VIRUSES (EXCEPT RETROVIRUSES) AND VIRAL DISEASES 3137

particularly children. An anterior opercular syndrome char-
acterized by paralysis of the masticatory, facial, pharyngeal,
and tongue muscles causing anarthria and impairment of
mastication and swallowing has been reported (262). Simi-
larly, the Foix-Chavany-Marie syndrome (i.e., automatic
voluntary dissociation of orofacial motility due to bilateral
anterior opercular infection) also has been described (263).
Patients with HSV encephalitis may have a variety of ocu-
lar manifestations. Visual sensory disturbances include hal-
lucinations, usually formed, and homonymous visual field
defects, usually incomplete and denser above because of se-
lective damage to the optic radiations in the temporal lobe
(and occasionally to the underlying optic tract), are present
in 10–20% of patients. Increased intracranial pressure that
may be associated with papilledema develops in about the
same percentage of patients (241). Papillitis occasionally oc-
curs; it may be bilateral or unilateral and may result in blind-
ness associated with optic atrophy (264). Ocular motor dis-
turbances that have been reported in patients with HSV
encephalitis include opsoclonus, bilateral ptosis and gaze
paresis, unilateral abducens nerve paresis, acute bilateral ex-
ternal ophthalmoplegia associated with a bilateral trigeminal
sensory neuropathy and bilateral facial pareses, downbeat
nystagmus, and recurrent oculogyric crises (265–275) (Fig.
57.12). Newman et al. (276) reported a unique case of brain
stem encephalitis caused by HSV-2. Neuro-ophthalmologic
findings included absent horizontal eye movements, intact
vertical gaze, intermittent ocular bobbing, bilateral facial
weakness, and bilateral decreased facial sensation. Postmor-
tem examination revealed a marked necrotizing encephalitis
primarily affecting the pons, with extension into the mesen-
cephalon, medulla, and cerebellum.
Intraocular inflammation affecting the retina, choroid,
optic nerve, or a combination of these structures occasionally
occurs concurrently with HSV encephalitis. The inflamma-
tion may be unilateral or bilateral, and it almost always oc-
curs in adults (251,277,278). Involvement of the optic nerve
in such cases almost always causes swelling of the optic
disc (278–280) (Fig. 57.13). The severity of the intraocular
inflammation varies considerably from a mild retinitis to a
severe obliterative chorioretinitis with obliterative vasculitis
and papillitis consistent with ARN (discussed earlier)
(251,281,282). Evidence of direct invasion of retinal tissue
and optic nerve by the virus is found in some cases
(277–280) (Fig. 57.14). Although the intraocular inflamma-
tion that occurs in the setting of HSV encephalitis, like the
encephalitis itself, is often unresponsive to treatment, some
patients experience a dramatic response to treatment with
antiviral agents (281).
There are no characteristic laboratory findings in patients
with HSV encephalitis. Although over 90% of patients who
develop HSV encephalitis have abnormalities of the CSF,
the findings are nonspecific. Intracranial pressure may be
normal or significantly increased (283). Initially, there may

Figure 57.12. External ophthalmoplegia from brain stem encephalitis caused by herpes simplex virus. The patient was a 62-
year-old man who initially developed complete, bilateral external ophthalmoplegia associated with a bilateral trigeminal sensory
neuropathy and bilateral facial weakness. An evaluation revealed evidence of infection with herpes simplex, and the patient
was treated with systemic corticosteroids. He gradually improved, but he had persistent ophthalmoplegia 10 months after the
onset of the illness. A, On attempted rightward gaze, there is moderate limitation of abduction of the right eye and adduction
of the left eye. The eyelids are being elevated manually because of moderate ptosis. The pupils react normally to both light
and near stimulation. B, On attempted leftward gaze, the patient has no movement of either eye. The patient’s ptosis is apparent.
C, On attempted downward gaze, there is some movement of both eyes. D, There is no movement of the eyes during attempted
upward gaze. (From Gordon CR, Leventon-Kriss S, Gutman I, et al. Brainstem encephalitis due to herpes simplex causing
permanent external ophthalmoplegia. Neuroophthalmology 1987;7:273–277.)
3138 CLINICAL NEURO-OPHTHALMOLOGY

Figure 57.13. Optic neuritis and retinitis associated with fatal herpes simplex encephalitis. The patient was a 75-year-old
man who initially reported blurred vision in the right eye and then developed a severe encephalitis. He died of cardiac arrest
shortly after the onset of the encephalitis. A, Appearance of the right ocular fundus at the time of visual loss. The optic disc
is swollen and pale, and there are several peripapillary hemorrhages. The retina is diffusely edematous and contains scattered
hemorrhages. Scattered aggregates of pigment are present in or beneath the retina in the region of the macula (arrow). B,
Fluorescein angiogram (late arteriovenous phase) of the right ocular fundus shows evidence of retinal edema, blocked fluores-
cence corresponding to intraretinal hemorrhages, and occlusion of peripheral aspects of retinal vessels. C, Fluorescein angiogram
(late venous phase) of the right ocular fundus shows marked leakage of dye from the optic disc with staining of the peripapillary
retina. Note late staining of occluded retinal vessels (arrows). (From Pepose JS, Kreiger AE, Tomiyasu U, et al. Immunocytologic
localization of herpes simplex type 1 viral antigens in herpetic retinitis and encephalitis in an adult. Ophthalmology 1985;
92⬊160–166.)

Figure 57.14. Invasion of the optic nerve and retina by herpes simplex virus in a patient with optic neuritis and retinitis in
the setting of herpes simplex encephalitis. The patient was a 48-year-old man who developed increasing lethargy, followed by
numbness and paresthesias of the left side of the body about 5 days after a minor head injury. He then had a generalized
seizure. Neurologic examination revealed the patient to be unresponsive, with both eyes being deviated to the left side. There
was evidence of a left hemiparesis. Ophthalmoscopic examination revealed blurred optic discs associated with dilation of retinal
veins and a few peripapillary retinal hemorrhages. The patient never improved and died about 7 days after admission. A, Section
through the right optic disc shows swelling of the axons, a marked inflammatory infiltrate in the nerve fiber bundles anterior
to the lamina cribrosa, and perivascular cuffing of disc vessels by inflammatory cells with thrombus formation in a dilated
vein. Hematoxylin and eosin, ⳯64. B, Higher-power view of the superficial portion of the right optic disc reveals inflammatory
cells in the vitreous overlying the disc and a lymphocytic infiltrate in the swollen disc tissue. Hematoxylin and eosin, ⳯400.
(Figure continues.)
 VIRUSES (EXCEPT RETROVIRUSES) AND VIRAL DISEASES 3139

Figure 57.14. Continued. C, Numerous intranuclear inclusion bodies are present within ganglion cells of the posterior retina.
Toluidine blue, ⳯640. D, Higher magnification of the retina shows intranuclear inclusion bodies (arrows) with peripherally
marginated chromatin. Toluidine blue, ⳯1400. E, Electron micrograph of an inclusion body reveals that the structure con-
tains numerous spherical particles with a central core morphologically consistent with herpes simplex virus. ⳯76,000. (From
Johnson BL, Wisotzkey HM. Neuroretinitis associated with herpes simplex encephalitis in an adult. Am J Ophthalmol 1977;
83⬊481–489.)

be a pleocytosis with a predominance of polymorphonuclear mass effect, or characteristic low-density contrast-enhancing

leukocytes (PMNs); however, within a few days, the CSF
shows a predominantly lymphocytic pleocytosis associated
with a moderate to severe increase in the concentration of
protein and a normal or low concentration of glucose (284).
Up to 85% of patients have red blood cells in the CSF despite
an atraumatic lumbar puncture (285). This finding probably
reflects the hemorrhagic nature of the pathologic process.
The EEG usually is abnormal in patients with HSV en-
cephalitis (284–286). Unilateral periodic lateralizing epilep-
tiform discharges are characteristic, although they are neither
common nor pathognomonic. The EEG also may show sharp
waves, variable spikes, and large-amplitude, irregular slow
activity. The finding of bilateral disturbances in the EEG is
a poor prognostic sign (287).
Neuroimaging studies are abnormal in most cases of HSV
encephalitis (244,287). Computed tomography (CT) scan-
ning may show changes consistent with edema, hemorrhage,
areas in one or both temporal and/or frontal lobes in adults
and older children (288). Neonatal HSV encephalitis does
not show this characteristic anatomic localization; instead,
the abnormalities tend to be more diffuse (288,289). MR
imaging usually shows both focal and generalized distur-
bances of both white and gray matter (290–292) (Fig. 57.15).
The most striking features on MR imaging are high signal
intensity in the temporal lobes, meningeal enhancement,
and changes consistent with intraparenchymal hemorrhage.
Diffusion-weighted MR imaging probably is more sensi-
tive in herpes encephalitis than conventional sequences
(292,292a). In preschool children, MR imaging occasionally
reveals multifocal or diffuse involvement of the brain with-
out the characteristic temporal lobe abnormalities (293). Sin-
gle-photon emission computed tomographic (SPECT) scan-
ning and positron emission tomographic (PET) scanning
may show evidence of pathology localized to the temporal
3140 CLINICAL NEURO-OPHTHALMOLOGY
Figure 57.15. MR imaging in herpes simplex encephalitis. A, Unen-
hanced T2-weighted axial MR image in a patient with biopsy-proven herpes
simplex encephalitis shows generalized hyperintensity in the left temporal
lobe, within which there are two hypointense areas (arrowheads), presum-
ably caused by hemorrhagic infarction. B, Unenhanced T2-weighted axial
MR image in another patient with biopsy-proven herpes simplex encephali-
tis shows marked hyperintensity in both temporal lobes. (From Demaerel
P, Wilms G, Robberecht W, et al. MRI of herpes simplex encephalitis.
Neuroradiology 1992;34⬊490–493.)
lobes and basal ganglia in patients with HSV encephalitis
(294–296). For example, Tanaka et al. (296) described a case
of HSV encephalitis in which PET scanning demonstrated
increased cerebral blood flow in the affected temporal lobe
accompanied by reduction in the cerebral oxygen extraction
fraction and the cerebral metabolic rate of oxygen (i.e., lux-
ury perfusion).
The neuropathology of HSV encephalitis is well described
(297). The gross appearance of typical HSV-1 encephalitis
is that of a hemorrhagic, necrotizing, focal encephalitis of
the inferior portions of one or both frontal and temporal
lobes (298). The other hemispheres, the cerebellum, and the
brain stem may show similar changes. The leptomeninges
overlying areas of cortical pathology may appear clouded,
congested, or both. Affected portions of the brain initially
show acute inflammation, congestion, hemorrhage, and soft-
ening (Fig. 57.16). Left untreated, HSV encephalitis pro-
duces frank necrosis and liquefaction that is so hemorrhagic
and destructive that the lesions resemble cortical contusions
or hemorrhagic infarcts. The hemorrhages gradually resolve,
leaving affected areas that are microcystic and gliotic, again
resembling old infarcts or contusions, except that lympho-
cytic perivascular inflammation may persist for an extended
period of time. Encephalitis caused by HSV-2 tends to be
more diffuse than that caused by HSV-1. In addition, the
lesions are often much less grossly necrotizing and hemor-
rhagic. The brain may even appear normal in some cases.
In newborns, the brain may be very congested, showing focal
cortical petechiae.
Microscopic examination of brains damaged by HSV en-
cephalitis reveals the necrotizing character of the inflamma-
tion (297). In addition, there is inflammation beyond areas
that appear grossly abnormal (241). At the earliest stage, the
histopathologic changes are mild and nonspecific. Capillar-
ies and other small vessels in the cortex and subcortical white
matter are congested, and petechiae are present. Some areas
show hemorrhagic necrosis and perivascular cuffing. The
perivascular cuffing becomes prominent in the second and
third weeks of infection. Glial nodules become evident after
the second week. The microscopic appearance becomes
dominated by evidence of necrosis and, eventually, inflam-
mation. The inflammation consists of a diffuse perivascular
subarachnoid mononuclear cell infiltrate, gliosis, and neu-
ronophagia. Many of the neurons, astrocytes, and oligoden-
drocytes contain intranuclear particles called Cowdry type
A inclusions. These inclusions have an eosinophilic homoge-
neous appearance and are often surrounded by a clear un-
stained zone beyond which is a rim of marginated chromatin.
Areas of lesser damage may nevertheless show only focal
aggregations of mesenchymal cells in the form of neurono-
phagic or microglial nodules.
The ultrastructural appearance of HSV encephalitis is
characterized by intranuclear paracrystalline arrays of viri-
ons in various stages of completion (297). There usually is
abundant fibrillary or granular electron-dense material inter-
mixed with spherical virions, reflecting the inefficient pro-
duction of viral components in the infected cell. Virions may
be found budding from the nucleus, enveloped by endo-
plasmic reticulum in the cytoplasm, or being extruded from
the cell surface.
IDIOPATHIC NEUROLOGIC SYNDROMES
HSV is implicated as a causative agent of several neuro-
logic disorders, including idiopathic peripheral facial nerve
paresis (Bell’s palsy), trigeminal neuralgia, atypical facial
pain syndromes, polyradiculitis, ascending or relapsing my-
elitis, meningitis, chronic encephalitis with epilepsy (Ras-
mussen’s encephalitis), and even temporal lobe seizures
 VIRUSES (EXCEPT RETROVIRUSES) AND VIRAL DISEASES 3141

Figure 57.16. Pathology of herpes simplex encephalitis of several weeks’ duration. A, A coronal section through the brain
of a 60-year-old man who survived 2 weeks after becoming febrile, experiencing seizures, and becoming decerebrate. The
inferior portion of the left temporal lobe anterior to the lateral geniculate body is shown here. There is an area of cortical
necrosis, and the underlying white matter has partly disintegrated. The process affects Meyer’s loop of the optic radiations.
B, In another patient who survived several weeks after the onset of the illness, the abnormal tissue in the more severely affected
left hemisphere (temporal lobe, insula, and cingulate gyrus) is beginning to disintegrate. Similar but much less severe changes
are seen in the right parahippocampal gyrus and in the insula. C, In a third patient who survived for several weeks after the
onset of herpes simplex encephalitis, the abnormal regions are cystic. Note extensive cavitation in the left temporal lobe and
insula. Much smaller lesions are seen in the right hemisphere. The cingulate gyri are also necrotic. (A, From Lindenberg R,
Walsh FB, Sacks JG. Neuropathology of vision: an atlas. Philadelphia, Lea & Febiger, 1973. B, and C, From Brownell B,
Tomlinson AH. Virus diseases of the central nervous system. In: Adams JH, Corsellis JAN, Duchen LW, eds. Greenfield’s
neuropathology. 4th ed. New York: John Wiley & Sons, 1984⬊260–303.)

(176,284,299–306). The associations are based on the
known predilection of HSV for neural tissue, on serologic
studies, and on the observation of occasional temporal rela-
tionships between the development of a straightforward
HSV infection and the occurrence of one of these syndromes.
Finally, HSV-1 and HSV-2 were reported in 46% of post-
mortem brain tissue samples from patients with multiple
sclerosis and in 28% of samples from control cases (307).
The significance of this finding is unknown; it may simply
reflect normal viral flora found in the brain, perhaps en-
hanced in the brains of multiple sclerosis patients by the use
of immunosuppressive agents and steroids (308).
Diagnosis
The diagnosis of primary HSV infection should be sus-
pected from the location and appearance of the mucocutane-
ous or ocular lesion. Patients with recurrent herpetic disease
have the added history of a previous infection in the same
general area. The diagnosis can rapidly be confirmed by
taking scrapings from the suspected lesion or lesions. The
scrapings are smeared, fixed with ethanol or methanol, and
stained with Giemsa or Wright preparations (155). The pres-
ence of multinucleated giant cells indicates infection with
either HSV or VZV. Scrapings or biopsy specimens exam-
ined cytologically or histopathologically may show charac-
teristic intranuclear inclusions. The material also can be ex-
amined for HSV antigens, using immunofluorescent
techniques (309), or for virus particles, using electron mi-
croscopy.
Serologic tests may be helpful in diagnosing primary HSV
infections, although they are not useful for presumed recur-
rent infection (155,310). HSV-1 and HSV-2 contain both
3142 CLINICAL NEURO-OPHTHALMOLOGY
type-specific and cross-reacting antigens that are useful for
both grouping and type discrimination. Thus, the develop-
ment of monoclonal antibodies to individual HSV antigens
permits more precise identification and typing of HSV iso-
lates (311). Finally, the use of molecular genetic techniques,
particularly PCR, to identify DNA specific for HSV-1 or
HSV-2 in tissue or in body fluids (including tears, aqueous
humor, vitreous, and CSF) of patients with presumed HSV
infection may be the most sensitive and specific way to diag-
nose both primary and recurrent infections of all types, par-
ticularly when the disease has an atypical presentation
(312–322).
The most accurate means of diagnosing HSV infection is
through tissue culture. Primary human embryonic kidney,
rabbit kidney, and human amnion cells readily support the
replication of HSV (155). Cytopathic changes usually de-
velop soon after such cells are inoculated with tissue or fluid
containing HSV, often within 48 hours if the inoculum con-
tains a large number of virus particles. Infected cells in tissue
culture become rounded and tend to clump together. Balloon
degeneration and formation of multinucleated giant cells
usually follow, particularly when the inoculum consists of
HSV-2. Enzyme Linked Virus Inducible System (ELVIS)
allows culture of HSV from ocular samples within 24 hours
(323).
The diagnosis of HSV encephalitis may be difficult. As
previously noted, it usually occurs in patients without any
previous or concurrent history of cutaneous HSV infection,
and it has no characteristic prodrome, no clinical features
that distinguish it from other encephalopathies, and no char-
acteristic laboratory findings. The results of both EEG and
neuroimaging studies are helpful; however, in many in-
stances, the diagnosis of HSV encephalitis rests with the
results of serologic and molecular genetic studies. Unfortu-
nately, isolation of HSV is quite difficult because the virus
is not typically present in stool, throat, urine, blood, or even
CSF during the acute stage of the disease. Because of the
difficulty in diagnosing HSV encephalitis from clinical find-
ings, neuroimaging studies, and laboratory evaluations, and
because of the delay that occurs in obtaining the results of
most serologic studies, brain biopsy was once the most
widely used means of definitively diagnosing the condition
in its acute stage. Now brain biopsy rarely is required for
diagnosis, which has been revolutionized by the availability
of CSF PCR analysis techniques (312–322). The use of PCR
instead of brain biopsy as the diagnostic standard for HSV
encephalitis has expanded awareness that mild or atypical
cases of HSV encephalitis are not uncommon (322). In addi-
tion to facilitating diagnosis, HSV PCR analysis of the CSF
may be useful in monitoring the adequacy of therapy (324).
For example, patients whose HSV PCR remains positive
after the completion of antiviral therapy should be assumed
to have persistent infection and should be treated for an addi-
tional 14 days (322). Quantitative PCR also may provide
information about prognosis (325,326). For example, pa-
tients with greater than 100 HSV DNA copies per microliter
of CSF are more likely than those with fewer copies to have
reduced level of consciousness, more severe abnormalities
on neuroimaging, a longer duration of illness, higher mortal-
ity, and more neurologic sequelae.
Treatment and Prognosis
A number of antiviral agents, both topical and systemic,
can be used to treat HSV infection in neonates, children,
and adults (155,160a). Most of these drugs interfere with
synthesis of HSV DNA. For mucocutaneous and visceral
HSV infections, acyclovir and its related compounds, fam-
ciclovir and valacyclovir, are the mainstay of therapy. The
most widely used drug is acyclovir (9-[2-hydroxyethoxy-
methyl]guanine). Infection of cells with HSV results in the
induction of a viral thymidine kinase that phosphorylates
acyclovir to a monophosphate form that is subsequently con-
verted to acyclovir triphosphate by cellular enzymes.
Acyclovir triphosphate is a potent inhibitor of HSV DNA
polymerase but has little cellular toxicity. The drug is avail-
able in oral, intravenous, and topical forms, none of which
has significant toxicity, although drug-induced disorienta-
tion, hallucinations, tremors, ataxia, and seizures occur in
rare patients (155). The major side effect associated with
intravenous acyclovir is transient renal insufficiency, usually
caused by crystallization of the compound in the renal paren-
chyma (155). This adverse reaction can be avoided if the
medication is given slowly over an hour and the patient is
well hydrated.
Several drugs, most of them topical preparations, can be
used to treat primary HSV keratitis (327–333). All are rea-
sonably effective in limiting the initial disease, but there is
evidence that treatment with oral acyclovir is associated with
a lower incidence of recurrent disease (330–333).
HSV encephalitis that is not treated has a mortality rate
of over 75%, with only about 2.5% of affected patients re-
gaining normal neurologic function (334). Some of the neu-
rologic deficits in survivors of untreated HSV encephalitis
include dementia, impaired learning and memory, Kluver-
Bucy syndrome, and intractable seizures (335–338).
Acyclovir is the drug of choice for HSV encephalitis
(155,339,340). In general, the earlier the drug is begun and
the more alert the patient at the beginning of therapy, the
better the outcome (340); however, HSV encephalitis resis-
tant to acyclovir is not uncommon, particularly in immuno-
compromised patients with severe disease (341). Thus, 30%
of patients with HSV encephalitis treated with acyclovir
either die or have a severe neurologic deficit, and most of the
remaining 70% have persistent neurologic sequelae (333).
Some patients with HSV encephalitis experience a relapse
or recurrence of their disease despite apparently adequate
treatment (342–345). Choreoathetosis may be the first sign
of relapse of HSV encephalitis in children and is an indicator
of poor prognosis (346).
Because of the morbidity and mortality of treated HSV
encephalitis, because of the potential for relapse or recur-
rence despite treatment with acyclovir, and because new
antiviral drugs are constantly being developed, the physician
managing a patient with this condition should consult a spe-
cialist to determine the appropriate management of the pa-
tient.
 VIRUSES (EXCEPT RETROVIRUSES) AND VIRAL DISEASES
Although most patients who develop HSV encephalitis
do not have significant ocular sequelae, some develop pro-
gressive loss of vision from concomitant retinal vasculi-
tis, ARN, uveitis, or a combination of these phenomena
(278,347,348).
Prophylaxis
Because there is no proven human vaccine against HSV,
attempts at prophylaxis usually are directed toward avoiding
contact with infected lesions. Medical and dental personnel
can avoid direct contact with potentially infectious lesions by
wearing gloves. Patients with extensive known or presumed
HSV lesions should be isolated. Condoms should be worn
to prevent genital spread of the virus when one sexual partner
has active herpetic lesions or a history of recurrent genital
infections.
Varicella-Zoster Virus
Varicella-zoster virus (VZV) shares structural characteris-
tics with the other members of the family of herpesviruses
(241,349). This virus causes two distinct clinical diseases.
Varicella (from the Modern Latin diminutive of variola,
meaning ‘‘spotted’’), or chickenpox, is the primary infection
and results from exposure of a susceptible person to the
virus. It is a ubiquitous disease that is extremely contagious
but for the most part self-limited and harmless, primarily
consisting of a generalized exanthematous rash. Recurrent
VZV infection results in the more localized disorder called
herpes zoster, or ‘‘shingles.’’
Varicella (Chickenpox)
EPIDEMIOLOGY AND PATHOGENESIS
Chickenpox follows exposure of a susceptible seronega-
tive person to the virus, and it is the primary form of infec-
tion. It is a common infection of childhood, with 90% of
cases occurring in children less than 10 years old (349).
In tropical regions, however, infection with VZV is often
delayed, and chickenpox often does not occur until adult-
hood.
The incubation period of chickenpox ranges from 10–20
days but usually is about 2 weeks. Patients are infectious
beginning about 48 hours before the period of vesicle forma-
tion, and they remain infectious until all the vesicles are
crusted, usually about 4–5 days.
VZV is thought to be transmitted by the respiratory route
in most cases of chickenpox. The virus then replicates at
some as-yet-undefined site, after which it seeds the reticulo-
endothelial system, eventually producing viremia. The vire-
mia results in delivery of the virus to multiple sites, including
the skin, and it is the presence of VZV in subcutaneous
vessels that is responsible for the diffuse vesicular rash that
is the hallmark of chickenpox.
PATHOLOGY
The histopathologic characteristics of the mucocutaneous
lesions in chickenpox and herpes zoster are nearly identical.
3143
The vesicles affect the corium and dermis. As local viral
replication progresses, the epithelial cells undergo degenera-
tive changes characterized by ballooning. The plasma mem-
branes separating adjacent cells dissolve and the cells be-
come confluent, resulting in the formation of multinucleated
giant cells. The viral particles within these cells are seen as
eosinophilic intranuclear inclusions. In addition, necrosis
and hemorrhage appear in the superficial portion of the der-
mis in some cases. As the vesicle evolves, the collected fluid
becomes cloudy from the accumulation of PMNs, degener-
ated epithelial cells, and fibrin. Eventually, the vesicles rup-
ture and release the infectious fluid, or the fluid is gradually
resorbed, and the vesicle disappears (241).
CLINICAL MANIFESTATIONS
Chickenpox is a self-limited, benign disease, primarily of
childhood, that lasts only about 3–5 days in most immuno-
competent children. It may, however, be more severe and
even life-threatening in adults and in immunocompromised
persons of all ages, particularly those with cancer (350,351).
Chickenpox tends to occur in seasonal outbreaks in the
winter and spring, with epidemics every 2–4 years. It typi-
cally presents after an incubation period of about 14 days,
with the acute onset of a pruritic rash, low-grade fever, and
malaise (349), although a prodrome consisting of nonspe-
cific constitutional symptoms may occur 1–2 days before
the onset of the exanthem. Mucocutaneous lesions are the
hallmark of the disease. They consist of maculopapules, ves-
icles, and scabs in varying stages of evolution that initially
appear on the trunk and face but spread centripetally over
24–48 hours to other parts of the body, including the mucosa
of the oropharynx and the vagina. Successive crops of le-
sions continue to appear for 2–4 days. Both healthy and
immunocompromised patients who develop chickenpox
may develop neurologic complications of the disease.
Neurologic Manifestations. Acute cerebellar ataxia is
the most common neurologic disturbance associated with
chickenpox, occurring in about 1 in 4,000 cases of chick-
enpox in children less than 15 years old (241,349,352,353),
and it is the most common form of encephalitis caused by
VZV in the United States and in many other countries (352).
The ataxia usually develops within 1 week after the appear-
ance of the exanthem, but it may occur as long as 3 weeks
later, and it even may develop 1–3 weeks before the onset
of the rash (354,355). Patients in whom this complication
occurs experience progressive ataxia, dysarthria, vertigo,
tremor, dizziness, drowsiness, and vomiting associated with
fever. Neurologic signs in such patients include vestibular
nystagmus and cerebellar eye signs such as ocular dysmetria,
skew deviation, and saccadic intrusions. Neuroimaging stud-
ies usually show no major abnormalities, although Hurst
and Mehta (356) described a 4-year-old boy with varicella-
associated cerebellar ataxia in whom both CT scanning and
MR imaging showed changes consistent with focal cerebel-
lar edema and demyelination. CSF in patients with this syn-
drome usually demonstrates a lymphocytic pleocytosis asso-
ciated with an increased concentration of protein and a
normal concentration of glucose. The condition tends to be
3144 CLINICAL NEURO-OPHTHALMOLOGY

self-limited, resolving spontaneously within 2–4 weeks
(352).
Copenhaver (357) described a 3-year-old child who devel-
oped acute cerebellar ataxia and a bilateral anterior optic
neuritis 2 days after the onset of a typical varicella rash.
The patient’s visual acuity in both eyes initially dropped to
counting fingers; however, it eventually returned to normal.
The pathogenesis of varicella-associated acute cerebellar
ataxia is unclear, particularly as it is a nonfatal disease. It
may be immune-mediated or caused by direct viral invasion
of the CNS (358).
A diffuse meningoencephalitis occurs as a complication
of chickenpox in 0.1–0.2% of patients (359), but it is a much
more serious complication of the disease than is acute cere-
bellar ataxia (241,360,361). It usually occurs about 6 days
after the onset of the rash, but it may follow the rash by up
to 3 weeks (359), occur simultaneously with the rash, or
even precede the rash by up to 11 days (359).
Varicella meningoencephalitis is characterized by severe
headaches, fever, vomiting, disturbances of thought, and a
progressive decline in the level of consciousness and thus,
generally, is indistinguishable clinically from meningoen-
cephalitis caused by other viruses. Seizures, both focal and
generalized, are common (359,361). Neurologic examina-
tion in such patients may show a variety of signs, such as
stupor, coma, irritability, delirium, hyperventilation, hyper-
pyrexia, nuchal rigidity, cranial neuropathies (including ocu-
lar motor nerve pareses), pyramidal signs with or without
limb weakness, or a combination of these. Some patients
develop increased intracranial pressure, and some of these
patients develop papilledema. Selbst et al. (362) described
a 10-year-old girl who developed encephalitis 5 days after
the onset of typical chickenpox. The girl gradually recovered
over the next 10 days, but 3 weeks later, she reported eye
pain and had difficulty seeing. Visual acuity was found to
be counting fingers in the right eye and hand motions in the
left eye. Both optic discs were swollen and hyperemic (Fig.
57.17). The patient was given oral prednisone that was grad-
ually tapered over the next 4 weeks. Visual acuity slowly
improved in both eyes to 20/20 OD and 20/25 OS, but color
vision remained poor in both eyes, and both optic discs be-
came pale.
Larsen et al. (363) reported three cases of varicella en-
cephalitis that were characterized by parkinsonian features,
including shuffling gait, bradykinesia, cogwheel rigidity,
masked facies, severe dysarthric speech, and inability to
swallow. In all three patients, the encephalitis developed
7–14 days after typical chickenpox. MR imaging in these
patients showed high-intensity signal on both T1- and T2-
weighted images in the basal ganglia, with involvement of
the globus pallidus, caudate nucleus, and putamen. One of
the patients died shortly after the onset of neurologic mani-
festations; one had complete resolution of all neurologic
manifestations; the other showed substantial and continued
improvement.
The CSF in patients with diffuse varicella meningoen-
cephalitis may be normal, but it more commonly shows a
mild to moderate pleocytosis, usually less than 100 cells/
mm3, with a predominance of lymphocytes. The CSF pres-
sure may be normal or increased, the concentration of protein

Figure 57.17. Optic neuritis and encephalitis from varicella. The patient was a 10-year-old girl who developed encephalitis
5 days after the onset of typical chickenpox. Three weeks later, she reported eye pain and decreased vision in both eyes. Visual
acuity was counting fingers OD and hand motions OS. There was a left relative afferent pupillary defect. A, The right optic
disc is swollen and hyperemic. The left optic disc had a similar appearance. Visual acuity subsequently improved to 20/20
OD and 20/25 OS. B, The right optic disc is now pale. The previously observed swelling has resolved. The left optic disc
showed a similar appearance. (From Selbst RG, Selhorst JB, Harbison JW, et al. Parainfectious optic neuritis: report and review
following varicella. Arch Neurol 1983;40⬊347–350.)
 VIRUSES (EXCEPT RETROVIRUSES) AND VIRAL DISEASES
in the CSF may be normal or moderately increased, and the
concentration of glucose in the CSF is almost always normal.
Varicella meningoencephalitis usually lasts about 2–3
weeks before recovery begins, but 5–20% of patients experi-
ence a progressive neurologic deterioration that ends in
death, usually within 1 week after the onset of neurologic
symptoms and signs (359). Factors associated with increased
mortality include seizures, coma, and hyperpyrexia (364).
The remainder survive, but 15–25% have persistent neuro-
logic sequelae, including paresis of one or more limbs, per-
sistent seizures, retarded growth and development, distur-
bances of speech, and psychiatric disorders (364). Some
cases of acute varicella encephalitis develop into a chronic
encephalitis or encephalomyelitis that requires intermittent
short courses of systemic corticosteroids to keep the condi-
tion under control (365). Darling et al. (366) described four
children with post-varicella encephalitis. Three of these chil-
dren presented with parkinsonism and showed bilateral basal
ganglia lesions on neuroimaging; the fourth patient demon-
strated diffuse, multiple gray and white matter lesions.
A variety of pathologic changes are present in the CNS of
patients with varicella meningoencephalitis. Affected tissue
generally shows prominent inflammatory changes, including
perivenous edema and perivascular cuffing by lymphocytes,
plasma cells, and macrophages (364). Capillary endothelial
edema, petechiae, ring hemorrhages with necrosis of vessel
walls, perivascular demyelination, and inflammatory infil-
tration of the leptomeninges are all observed (364). Neuronal
damage is mild in most cases, but severe damage can occur.
Some cases are characterized pathologically by widespread
hemorrhages in the white matter of the brain and spinal cord
(367). Such cases may be considered a form of hemorrhagic
leukoencephalitis. The pathogenesis of varicella encephalitis
is unclear, but most cases are probably immune-mediated
(368).
Some cases of encephalopathy that occur during or after
chickenpox are neither immune-mediated nor caused by di-
rect virus invasion of the CNS. Intracranial hemorrhage
caused by hematologic dysfunction, such as thrombocyto-
penia or disseminated intravascular coagulation, may pro-
duce focal or diffuse neurologic manifestations (369), and
various nonneurologic disorders that may accompany severe
chickenpox, such as hyperthermia, water intoxication with
hyponatremia, circulatory collapse, and severe pneumonia,
may produce an acute encephalopathy (368). Reye syn-
drome, another cause of acute encephalopathy associated
with chickenpox, is discussed separately later.
The meningitis that occurs in association with chickenpox
usually is aseptic and self-limited (359,360). There are no
clinical or laboratory features that distinguish it from aseptic
meningitis caused by other organisms, except that it occurs
within 1–3 weeks after the onset of otherwise typical chick-
enpox. Most patients are febrile and complain of headache
and stiff neck. Focal neurologic findings, including cranial
neuropathies, are extremely rare. Singer (370) described
three children who experienced acute bacterial meningitis
shortly after the development of typical chickenpox. All
three children initially were thought to have a postinfectious
aseptic meningitis until their CSF was examined.
3145
Myelitis associated with chickenpox is extremely rare and
accounts for only about 3% of all the neurologic complica-
tions of the infection (364). Both an ascending myelitis and
a transverse myelitis can occur (371–373). The myelitis of
chickenpox usually develops 1–2 weeks after the onset of
the rash. The typical clinical picture consists of acute bilat-
eral lower extremity weakness associated with sensory loss
and, in some cases, urinary and fecal incontinence. Reflexes
usually are increased, but they may be normal or even de-
creased. The CSF usually is abnormal, with a pleocytosis
that generally is lymphocytic and less than 160 cells/mm3
and a normal or increased protein concentration. Most pa-
tients make a full recovery (241).
Caution must be used when ascribing myelitis to chick-
enpox. Rösener et al. (374) described a patient who, 8 weeks
after presumed chickenpox-associated myelitis, developed
optic neuritis and was eventually diagnosed with multiple
sclerosis.
Chusid et al. (375) described a 5-year-old child who devel-
oped transverse myelitis associated with bilateral retrobulbar
optic neuritis (Devic syndrome; neuromyelitis optica) 9 days
after developing a typical varicella rash. The child’s vision
dropped to no light perception in both eyes, but it gradually
recovered to ‘‘normal’’ over 6 months. No mention was
made in the article about the eventual appearance of the optic
discs. Similar cases have been described by other authors
(371,376). In some of these cases, vision has improved dra-
matically after treatment with steroids; in others, there has
been no significant improvement regardless of treatment.
Guillain-Barré syndrome accounts for about 7% of all
neurologic complications of otherwise typical chickenpox
(364,377). Neurologic symptoms and signs typically begin
7–20 days after the appearance of the rash and consist of
flaccid limb paralysis, often with prominent proximal weak-
ness. These and other neurologic manifestations of chick-
enpox-related Guillain-Barré syndrome are identical with
those of idiopathic Guillain-Barré syndrome. These manifes-
tations include ophthalmoplegia, ptosis, dilated and nonreac-
tive or poorly reactive pupils, bilateral facial weakness,
weakness of the bulbar musculature, areflexia, autonomic
dysfunction, and sensory symptoms, including numbness
and paresthesias (364). The Fisher variant of Guillain-Barré
syndrome, characterized by ophthalmoplegia, areflexia, and/
or ataxia, also may be associated with chickenpox (378). The
prognosis is said to be favorable, with complete recovery in
almost all patients.
Children who develop otherwise typical chickenpox may
develop Reye syndrome, also called acute nonicteric fatty
hepatoencephalopathy (379). This condition is characterized
clinically by the acute onset of severe recurrent vomiting,
restlessness, irritability, and a progressive decrease in con-
sciousness over several hours. Raised intracranial pressure,
often with papilledema, generalized hypertonia without focal
signs, hyperventilation, sympathetic hyperactivity, and de-
corticate or decerebrate posturing then occur. Liver damage
is manifested by hepatomegaly associated with a marked
increase in the serum hepatic transaminases (AST and ALT)
and in the plasma ammonia concentration, although the bili-
rubin level usually is normal and jaundice is rare. Neuroim-
3146 CLINICAL NEURO-OPHTHALMOLOGY
aging studies show changes consistent with cerebral edema
with small ventricles and no evidence of a mass lesion. The
CSF usually is normal, except for the increased intracranial
pressure. EEG shows nonspecific diffuse slowing. Death re-
sults from cerebral edema and occurs in almost all untreated
patients. Early recognition and prompt aggressive therapy
to lower intracranial pressure and restore metabolic distur-
bances are associated with a mortality rate that is less than
20% but still significant.
Reye syndrome is mainly a disease of childhood, although
adults occasionally are affected. It almost always follows
a presumed or known viral infection, with the two most
frequently implicated viruses being influenza and VZV
(380). Indeed, it has been estimated that 7–28% of cases of
Reye syndrome are associated with chickenpox and that
Reye syndrome accounts for about 5% of all neurologic com-
plications of the disease (369). The cause of Reye syndrome
in most cases appears to be the salicylates used to treat the
fever that accompanies the chickenpox. The mechanism by
which aspirin and other salicylates produce this encephalop-
athy is unclear.
Although an acute hemiparesis occurring weeks to months
after herpes zoster ophthalmicus (HZO) and, to a lesser ex-
tent, nonophthalmic herpes zoster is a well-known phenome-
non, an identical syndrome of delayed cerebral vasculitis
also occurs occasionally in patients after chickenpox
(381–389). Most patients who develop delayed cerebral vas-
culitis after chickenpox are less than 10 years old (384,
386,387), but some cases occur in adults (382,388).
The neurologic manifestations of delayed cerebral vascu-
litis after chickenpox begin 1–3 months after the onset of
the rash. The most common deficit is a hemiparesis, but a
homonymous visual field defect, often a complete hemia-
nopia, may be present (382). Seizures, lethargy, and somno-
lence may occur but are uncommon. Neuroimaging studies
in most patients show an infarct in the basal ganglia and
internal capsule, although some patients develop infarcts in
other areas, including the frontal, parietal, and occipital lobes
(382,385,386). Cerebral arteriography typically shows seg-
mental narrowing and irregularity in various intracranial ves-
sels with distal slowing of flow (Fig. 57.18), although some
patients have completely normal findings (384,385). Most
patients recover completely or nearly completely, regardless
of treatment (384).
The pathogenesis of delayed cerebral vasculitis after
chickenpox is unclear. It may be an autoimmune phenome-
non, produced by the formation of antigen–antibody com-
plexes in one or more intracranial arteries or a direct infec-
tion of these arteries by VZV that is transported through
trigeminal—vascular or sympathetic nervous system—vas-
cular pathways and that produces inflammation and throm-
bosis in affected arteries (384).
Patients may develop optic neuritis in association with
chickenpox. In some cases the optic neuritis occurs in the
setting of acute cerebellar ataxia, diffuse encephalitis, or
transverse myelitis (357,362,371,375), but in others it occurs
as an isolated phenomenon (371,390,391). The visual loss
begins 2 days to 6 weeks after the appearance of the varicella
rash. Most cases occur in children, the population in whom
chickenpox is most common, but some cases occur in adults
(371). Almost all patients lose vision in both eyes, with vi-
sion dropping to between hand motions and no light percep-
tion. Optic disc swelling is almost always present. Visual
acuity often returns to normal or near normal, but permanent
visual deficits, including impairment of color vision, visual
field defects, and optic atrophy, almost always remain.
Taylor and Ffytche (392) reported an unusual case of optic
disc pigmentation associated with a visual field defect in a
16-year-old girl after an attack of chickenpox. The patient
apparently developed an acute defect in the inferior portion
of the field of vision of the left eye about 4 days after the
appearance of the varicelliform rash. She was examined
within a few weeks, at which time visual acuity was 20/15
OD and 20/20 OS. Pupillary reactions were said to be nor-
mal, but there was a dense inferonasal quadrantic defect in
the visual field of the left eye, and the superotemporal area of
the optic disc was said to be pale. Subsequent examinations
revealed pigmentation in the previously pale portion of the
disc, unassociated with change in visual acuity or visual
field. The authors hypothesized that the disc pigmentation
resulted from migration of retinal pigment epithelium after
an attack of optic neuritis associated with chickenpox. How-
ever, several aspects of this case are confusing, including
the apparent absence of a relative afferent papillary defect
(RAPD) in the affected eye and the presence of optic disc
pallor only 1–2 weeks after the onset of the field defect.
A unilateral, dilated, and fixed or poorly reactive pupil
(internal ophthalmoplegia) may occur after an attack of
chickenpox (393). The condition usually develops within 14
days after the skin eruption. Many patients have an associ-
ated iritis or iridocyclitis, and rare patients have an accompa-
nying meningoencephalitis. Most of these cases appear to
result from damage to the ciliary ganglion or short posterior
ciliary nerves, producing a tonic pupil (393). In some cases,
however, local inflammation and accompanying ischemia
from vasculitis damage the iris sphincter and produce the
condition.
Butler (394) reported the case of a 15-year-old girl who
was recovering from chickenpox when she developed ‘‘com-
plete paralysis of the sphincter iridis of both eyes, causing
the pupils to be fully dilated. Accommodation was also para-
lysed.’’ No mention was made of any ptosis or ocular motor
disturbance. The patient recovered completely within 6
weeks. Although it is possible that this patient had a transient
bilateral tonic pupil syndrome, we suspect that the condition
was caused by inadvertent topical contact of the eyes with
a parasympathomimetic substance.
Third nerve palsy has been reported in patients with chick-
enpox. In some cases the palsy is associated with other evi-
dence of encephalitis (395), whereas in others it occurs as
an isolated phenomenon (396) (Fig. 57.19).
Liioi and Aiello (397) reported a case of pseudotumor
cerebri associated with chickenpox in a 5-year-old girl. The
patient initially had a typical varicella rash, following which
she reported bifrontal headaches associated with chills,
fever, and anorexia, with concurrent weight loss. She then
reported poor vision in the left eye. An examination revealed
 VIRUSES (EXCEPT RETROVIRUSES) AND VIRAL DISEASES 3147

Figure 57.18. Delayed cerebral vasculitis after varicella in an adult. A, Right common carotid digital subtraction arteriogram
(anteroposterior view) in a 43-year-old woman who developed aphasia and a right hemiparesis about 3 weeks after she had
chickenpox that she acquired from her grandson. The arteriogram shows segmental narrowing of the A-1 segment of the right
anterior cerebral artery (small arrows) and the M-1 segment of the right middle cerebral artery (large arrow). There is also
segmental beading of distal branches of the middle cerebral artery (open arrows). B, T1-weighted axial MR image after injection
of paramagnetic contrast material in a 22-year-old woman who developed an acute right hemiplegia, right homonymous
hemianopia, and right-sided hemianesthesia 5 weeks after experiencing an attack of varicella during a community outbreak.
The scan shows changes consistent with a widespread left-sided cortical and subcortical infarction. A cerebral arteriogram
showed occlusion of the supraclinoid portion of the left internal carotid artery. (A, From Schwid S, Ketonen L, Betts R, et al.
Cerebrovascular complications after primary varicella-zoster infection. Lancet 1992;340⬊669. B, From Leopold NA. Chickenpox
stroke in an adult. Neurology 1993;43⬊1852–1853.)

visual acuity of 20/30 OD and light perception without pro-
jection OS. CSF pressure was 550 mm of water. The CSF
was otherwise normal. The patient was treated with systemic
corticosteroids, and her papilledema gradually resolved; as
it did, vision improved in the left eye. Final visual acuity
was 20/30 OU. In view of the history of chills and fever, as
well as the abrupt loss of vision in the left eye with eventual
recovery, we are inclined to consider this a case of pseudotu-
mor cerebri complicated by perioptic neuritis.
Facial nerve paresis may occur following an attack of
chickenpox (398–401). In some cases the paresis is an iso-
lated phenomenon, but in others it is associated with other
neurologic deficits. The facial weakness may occur as early
as 5 days before the development of the typical rash or as
late as 16 days after it has developed. Whether the facial
nerve paresis in these patients is directly related to chick-
enpox with secondary inflammation of the facial nerve (per-
haps in the facial canal) by VZV or is an autoimmune phe-
nomenon is unclear.
Ocular Complications. A variety of isolated ocular
complications may occur after chickenpox, including den-
dritic keratitis (402), branch retinal artery occlusion (403),
central retinal artery occlusion (404,405), and retinal vascu-
litis (406). Some patients develop a nonspecific necrotizing
retinitis (407,408), whereas others develop typical ARN
(178,409–411).
Although the primary intraocular complications of chick-
enpox are retinal, choroiditis can occur after chickenpox. In
some cases, the choroiditis is multifocal (407). In others, it
is unifocal (412,413).
3148 CLINICAL NEURO-OPHTHALMOLOGY

Figure 57.19. Oculomotor nerve paresis after chickenpox. The

patient was a 2-year-old girl who developed a paresis of the left
oculomotor nerve 2 weeks after a mild attack of chickenpox. A,
External appearance of child. Note head tilt to the left with face
forward. B, Eye movements in nine primary positions of gaze. There
is limitation of elevation of the left eye, particularly in adduction.
Note isocoric pupils. There is no evidence of ptosis. (From Sharf
B, Hyams S. Oculomotor palsy following varicella. J Pediatr Oph-
thalmol 1972;9:245–247.)

CONGENITAL AND PERINATAL VARICELLA INFECTION drome, and nystagmus, are common, as are CNS manifesta-
tions, particularly mental retardation, seizures, and hydro-
About 5–7% of women of childbearing age are seronega-
cephalus (417–423). Neuropathologic examination in such
tive for previous VZV infection (414). Prenatal screening of
cases reveals destructive and inflammatory lesions through-
women who are uncertain whether they have had chickenpox
out the CNS, sometimes associated with heterotropias and
reveals that about 30% are seronegative for anti-VZV anti-
other congenital malformations (423).
bodies (415). These figures are of great importance because
Neonatal (perinatal) varicella infection occurs when ma-
of the potentially devastating systemic, neurologic, and ocu-
ternal chickenpox occurs within 5 days before delivery or
lar defects caused by both congenital and perinatal varicella
up to 48 hours after delivery (424,425). It is characterized
infection. Even women who are seropositive for VZV may
by progressive involvement of the visceral organs, especially
develop chickenpox during pregnancy (416).
the lung, and occurs because the newborn has no maternal
Congenital defects that include both ocular and CNS man-
antibodies against VZV and has an immature immune sys-
ifestations can occur in infants born to mothers who experi-
tem. The condition has a mortality rate of about 30%.
ence chickenpox during the first 6 months of pregnancy
(417–423). Affected infants have a characteristic cicatricial
cutaneous scar that usually corresponds to the territory of a Herpes Zoster
specific dermatome and is associated with corresponding EPIDEMIOLOGY
limb hypoplasia and contracture. Ocular abnormalities, in-
cluding microphthalmia, cataracts, chorioretinal scarring, Herpes zoster results from reactivation of latent VZV in
optic atrophy, hypoplasia of the optic nerve, Horner syn- patients who have experienced previous VZV infection.
 VIRUSES (EXCEPT RETROVIRUSES) AND VIRAL DISEASES
Thus, except for rare infants who develop herpes zoster as
the primary clinical manifestation of latent VZV infection
acquired transplacentally during intrauterine life (426), the
disease occurs only in patients who have had chickenpox or
who have experienced previous subclinical infection with
VZV and who are seropositive for the virus.
Herpes zoster can develop at any age, although it primarily
affects adults (427), with 75% of cases occurring in persons
over the age of 45; the rate in patients over 60 is 5–10 cases
per 1,000 persons (428). The condition is rare in children
under 15 years old, with less than 10% of cases occurring
under age 20. African-Americans have a significantly lower
risk of developing herpes zoster than Caucasians (429).
Certain factors appear to increase the risk of an attack of
herpes zoster. Exposure to patients with active VZV infec-
tion does not seem to play a role, but the condition is more
frequent with advancing age and also occurs more com-
monly in patients who are immunocompromised by drugs
or diseases such as AIDS, lymphoma, and leukemia
(427,430–433). Patients who have cutaneous anergy or have
undergone radiation therapy, splenectomy, chemotherapy,
bone marrow or renal transplantation, or a combination of
these procedures are also at risk (434,435). In patients who
have received local radiation therapy, the zosteriform rash
develops in the previously irradiated region in over 50% of
cases (436). Other risk factors for the development of herpes
zoster include diabetes mellitus, systemic lupus erythemato-
sus, lymphoproliferative cancers other than lymphoma and
leukemia, non-lymphoproliferative cancers, surgery, and
trauma that may seem quite minor (437,438).
In patients with cancer who develop herpes zoster, the site
of the primary neoplasm tends to correlate with the affected
dermatome (436). For example, patients with GI or GU ma-
lignancies tend to have lower lumbar and sacral dermatome
involvement, whereas patients with breast cancer and lung
cancer tend to develop herpes zoster in a thoracic der-
matome.
About 10% of the population around the world ultimately
experience an attack of herpes zoster (439). Most patients
experience only one attack, but about 4% have a second
attack and rare patients suffer a third.
PATHOGENESIS AND PATHOLOGY
The generally accepted theory of the pathogenesis of
herpes zoster is that proposed by Hope-Simpson (440), who
suggested that during the primary infection by VZV (i.e.,
chickenpox), a viremia occurs. The virus reaches the skin
and is then transported along the sensory nerve fibers to
various sensory ganglia, including both the trigeminal and
geniculate ganglia, where it becomes latent in neurons. Sub-
sequently, the virus becomes reactivated either sporadically,
with no clear precipitating event, or after some specific trig-
gering stimulus (discussed previously). Once reactivation
occurs, the virus spreads antidromically along the sensory
nerve to return to the skin, where it produces the vesicular
rash of herpes zoster associated with pain in the appropriate
dermatome. This theory is supported by pathologic and mo-
lecular genetic findings in patients with the disease
3149
(441–445). For example, herpesvirus particles were detected
in Schwann cells in the trigeminal ganglion of a patient who
died after developing HZO (441).
Herpes zoster is characterized not only by the pathologic
cutaneous and subcutaneous changes normally seen in pa-
tients with chickenpox but also by acute inflammation of
the affected sensory ganglion and nerve (447). The ganglion
shows intense lymphocytic infiltration with necrosis of nerve
cells and fibers, endothelial cell proliferation and lympho-
cyte cuffing of small vessels, focal hemorrhage, and inflam-
mation of ganglion sheaths. Acidophilic intranuclear inclu-
sion bodies are seen in satellite cells and neurons. The
inflammatory and degenerative changes can be traced dis-
tally to branches affecting the skin and proximally to the
posterior nerve roots and adjacent regions of the spinal cord
or brain stem.
Direct invasion by VZV, combined with the inflammatory
and immune reaction produced by the host, contribute to the
ocular complications that occur in some patients with HZO
as well as in some patients with nonophthalmic herpes zos-
ter. Unique to HZO is a plasma cell and lymphocytic infiltra-
tion of the gasserian ganglion, the uveal tract of the eye,
and the retrobulbar tissues, particularly the posterior ciliary
nerves and vessels (447). During the early stages, the inflam-
mation is nongranulomatous and reversible. Ultimately, it
becomes granulomatous, being characterized by epithelioid
and giant cells and by areas of necrosis. VZV particles can
be identified in some of the tissues. A granulomatous angiitis
with inflammation and infarction of tissue supplied by af-
fected vessels also may occur, producing severe ocular, or-
bital, and neurologic deficits (448). Thus, the end stage of
herpes zoster in some tissues is a chronic granulomatous
reaction; in other tissues, an ischemic vasculitis dominates
the pathologic picture.
CLINICAL MANIFESTATIONS
Herpes zoster usually is characterized by a unilateral ve-
sicular eruption that has a dermatomal distribution, although
some patients never develop any cutaneous manifestations
of the disease (449). In contrast to chickenpox, herpes zoster
occurs mainly in adults, does not have a seasonal or yearly
variation in incidence, and is not more frequent during pe-
riods of varicella epidemics.
Systemic Manifestations. The onset of the disease is
generally heralded by severe pain, itching, or paresthesias
in the affected dermatome. Thoracic and lumbar dermatomes
are most commonly affected, and the pain occasionally is
severe enough that it is thought to be angina or caused by
cholecystitis (450). About 48–72 hours after the onset of
the sensory symptoms, typical skin lesions appear and may
be associated with constitutional symptoms, such as malaise,
headache, and fever (349). Local lymphadenopathy may be
present. The skin lesions consist of erythematous papules
that rapidly evolve into a vesicular rash (Fig. 57.20). Some
vesicles coalesce to form large bullae. Most, however, be-
come pustules within about 3 days after their appearance.
In the immunocompetent patient, the lesions continue to
form over a period of 10 days. The pustules eventually begin
3150 CLINICAL NEURO-OPHTHALMOLOGY
Figure 57.20. The localized rash of herpes zoster. Note the characteristic
vesiculobullous appearance and a tendency for coalescence.
to dry, crust formation occurs, and the crusts fall off within
2–3 weeks after the appearance of the rash. Thus, the total
duration of active disease usually is about 10–15 days, al-
though it may take as long as 1 month for affected skin to
return to normal.
When herpes zoster occurs in a patient who is immuno-
compromised by age, drugs, or disease, the condition tends
to be more severe than it is in an otherwise healthy person.
Cutaneous lesions may continue to form over a 2-week pe-
riod, and scabbing may not occur until 3–4 weeks or even
longer after the initial manifestations of the disease (451).
Patients with lymphoproliferative malignancies who de-
velop herpes zoster are at particular risk for cutaneous dis-
semination and visceral involvement. Such patients also may
develop neurologic complications (discussed later); how-
ever, despite the severity of the infection, it is rarely fatal,
even in these debilitated patients.
Chronic herpes zoster occasionally occurs in immuno-
compromised patients, particularly those with AIDS (349).
In such cases, there is persistent lesion formation, with lack
of healing of existing lesions.
Neurologic Manifestations. As with chickenpox, pa-
tients with herpes zoster may develop extracutaneous mani-
festations of the disease, and, as with chickenpox, the most
significant of these manifestations involve the CNS. In fact,
herpes zoster is associated with more neurologic complica-
tions than is chickenpox, and the neuro-ophthalmologic im-
plications of the disease thus are more significant. The com-
plications occur in both normal and immunocompromised
persons and, like herpes zoster itself, are more common in
the elderly than in the young (369).
One of the most significant neurologic complications of
herpes zoster, occurring in about 5% of patients with the
disease, is segmental weakness affecting the muscles of the
limbs, sphincters, abdomen, and diaphragm (452,453). The
interval between the development of the skin rash and the
onset of muscle weakness is variable and ranges from less
than 1 day to 4 months, but it is less than 2–3 weeks in most
patients. The muscle weakness corresponds to the der-
matome affected by the rash in almost all patients and tends
to occur suddenly, peaking within hours to days. Muscles
supplied by the thoracic nerves are most often affected, but
paresis of muscles supplied by the cervical or lumbosacral
nerves is more often clinically apparent (455). Weakness is
generally unilateral, although bilateral upper and lower limb
weakness can occur. Abdominal muscle weakness tends to
be generalized, whereas diaphragmatic paralysis tends to be
unilateral and is most often associated with cervical zoster.
Bladder or anal dysfunction may occur as an isolated com-
plication of herpes zoster or in the setting of encephalitis or
myelitis (456). The typical presentation is unilateral sacral
zoster that is followed by urinary retention, cystitis, or both,
combined with loss of anal and bladder sensation and incon-
tinence (457).
Examination of the cerebral spinal fluid (CSF) in patients
with segmental motor weakness is nondiagnostic but may
reveal a moderate lymphocytic pleocytosis associated with
an increase in protein concentration (369,454). Radiologic
studies in patients with sphincter weakness may show a blad-
der that is distended, atonic, or both. Detrusor paralysis may
be present in such cases.
The prognosis of herpes zoster-related segmental motor
weakness is good, with complete recovery occurring in
55–75% of cases, usually within 6–12 months (453). Only
about one in six patients is left with permanent paralysis,
most often in the distal muscles. The prognosis for patients
with sphincter involvement is excellent, with almost all pa-
tients recovering completely within several weeks to months
(369).
The pathogenesis of herpetic segmental motor weakness
is unclear. Direct spread of virus from the sensory ganglia
to the anterior horn cells, anterior nerve roots, peripheral
nerves, or a combination of these sites is likely in most pa-
tients (453), but this mechanism would not seem to explain
the 10% of cases in which the skin rash and the muscle
weakness are dissociated (458).
Herpes zoster not infrequently affects the cranial nerves.
In some patients, a single nerve is damaged; in others, multi-
ple cranial neuropathies occur (459). The most frequently
affected nerve is the facial nerve, involvement of which
causes a peripheral facial nerve paresis that may be isolated
or associated with other cranial neuropathies (460–462).
When the facial paresis is isolated, it may be diagnosed as
‘‘idiopathic Bell’s palsy,’’ and its relationship to VZV may
be overlooked (460,461).
Some patients develop a peripheral facial nerve paresis
associated with pain in the ipsilateral ear and the develop-
ment of vesicles on the pinna and in the external auditory
canal. Many of these patients also have loss of taste in the
anterior two thirds of the tongue and dysfunction of the ipsi-
lateral vestibulocochlear nerve, causing deafness, tinnitus,
vertigo, and unsteadiness (369,463). This condition is called
herpes zoster oticus or the Ramsay Hunt syndrome
 VIRUSES (EXCEPT RETROVIRUSES) AND VIRAL DISEASES
(460,464–466). The Ramsay Hunt syndrome may occur as
an isolated phenomenon, in association with other cranial
neuropathies, or as part of a localized brain stem encephalitis
(467). Keane (468) described a 57-year-old man who devel-
oped an acute left trochlear nerve paresis about 2 weeks
after the onset of left-sided herpes zoster oticus (Fig. 57.21).
About 1 week later, he developed a mild left abducens pa-
resis. Both ocular motor nerve pareses eventually resolved,
but the patient had persistent left-sided facial weakness and
evidence of aberrant regeneration of the facial nerve. Carroll
and Mastaglia (469) described a 55-year-old man who devel-
oped an acute left optic neuropathy 9 days after the onset
of an otherwise typical Ramsay Hunt syndrome character-
ized by left-sided facial paresis and left ocular motor nerve
pareses. Visual acuity in the left eye dropped to counting
fingers. There was a left RAPD, but the left optic disc ap-
peared normal. The patient’s visual acuity eventually im-
proved to 20/30, although the left optic disc became pale.
A necrotizing herpetic retinopathy has also been reported
with Ramsay Hunt syndrome (470).
Rare patients develop a typical Ramsay Hunt syndrome
except that cutaneous auricular lesions never develop (471).
Such patients develop severe facial pain and herpetic lesions
on the tongue but no lesions on the pinna or in the external
auditory canal.
The pathogenesis of herpes zoster oticus seems to be reac-
Figure 57.21. Herpes zoster oticus associated with trochlear nerve pa-
resis. The patient was a 57-year-old man who developed an acute left troch-
lear nerve paresis about 2 weeks after the onset of left-sided herpes zoster
oticus. A, The patient has marked left-sided facial weakness. B, Resolving
skin lesions in the left auricle. C, Left hypertropia in primary position. D,
Left eye shows limitation of depression in adduction consistent with weak-
ness of left superior oblique muscle. (From Keane JR. Delayed trochlear
nerve palsy in a case of zoster oticus. Arch Ophthalmol 1975;93⬊382–383.)
3151
tivation of latent virus in the geniculate ganglion that is trans-
mitted in retrograde fashion to the peripheral nerve endings
of the facial nerve (445). Ganglionitis and neuritis in the
narrow facial (fallopian) canal cause facial nerve paresis,
whereas more extensive inflammation with spread to the
adjacent vestibulocochlear nerve produces auditory and ves-
tibular dysfunction and may lead to a full-blown Ramsay
Hunt syndrome. Thus, it is not surprising that patients in
whom this condition occurs may show abnormal enhance-
ment along the pathway of the facial nerve on MR imaging
(461,463,472,473).
Herpes zoster may affect one, two, or all three divisions
of the trigeminal nerve. When the maxillary or mandibular
divisions of the trigeminal nerve are affected, skin lesions
develop in the distribution of these branches (474). In addi-
tion, intraoral vesicles develop on the palate, tonsillar fossa,
floor of the mouth, and tongue. Such patients may eventually
develop postgustatory flushing and sweating caused by dam-
age to the auriculotemporal nerve (475), and rare patients
develop an ipsilateral Horner syndrome (476).
The ophthalmic division of the trigeminal nerve is affected
in 7–15% of cases of herpes zoster (446), and the resulting
condition—herpes zoster ophthalmicus—has significant
visual and neuro-ophthalmologic manifestations (446,477).
HZO tends to occur most often in elderly men, but about
7% of patients who develop HZO are children (478). The
condition is almost always unilateral, but it may be bilateral
(479), particularly in patients with AIDS (480). In patients
with bilateral HZO, one side usually becomes affected sev-
eral days to weeks before the other, but we have seen bilat-
eral HZO that began simultaneously on the two sides.
HZO occurs throughout the world. Although most cases
of HZO occur in healthy adults, an increasing number are
immunosuppressed (446,481,482). Indeed, HZO may be the
presenting sign of AIDS (483,484). Patients with various
malignancies, particularly lymphoma, and patients receiving
immunosuppressive therapy for cancer or after organ trans-
plantation may also be at increased risk for developing this
condition (482). Other predisposing factors include tubercu-
losis, malaria, syphilis, and trauma (485). Also, dysproteine-
mias and paraproteinemias are more common in patients
suffering from HZO than in the normal population (486).
HZO may affect the frontal nerve, nasociliary nerve, lacri-
mal nerve, or any combination of these. The frontal nerve,
which branches into the supratrochlear and supraorbital
nerves that supply the skin of the upper eyelid, forehead,
and superior conjunctiva, is most often involved (487), re-
sulting in characteristic vesicles in the frontal region and
on the eyelid. The nasociliary nerve, which innervates the
anterior and posterior ethmoid sinuses, the skin of both eye-
lids, the conjunctiva, sclera, cornea, iris, and choroid, and
which transmits sympathetic fibers to the ciliary ganglion,
also supplies the skin of the tip of the nose. Involvement of
this nerve may produce characteristic vesicles at the tip of
the nose, called Hutchinson’s sign (488) (Fig. 57.22). The
lacrimal nerve supplies the lacrimal gland and the temporal
part of the upper eyelid. It is the least commonly affected
of the three nerves.
As is the case with herpes zoster elsewhere, HZO usually
3152 CLINICAL NEURO-OPHTHALMOLOGY

Figure 57.22. Herpes zoster ophthalmicus with involvement of both the frontal and the nasociliary nerves. A, On the right
side in a 4-year-old girl. B, On the left side in a 7-year-old boy. Note involvement in both children not only of the upper eyelid
and frontal region, indicating involvement of the frontal nerve, but also of the tip of the nose (Hutchinson’s sign), indicating
involvement of the nasociliary nerve. (A, From Schwartz DE. Herpes zoster ophthalmicus with nasociliary nerve involve-
ment. Am J Ophthalmol 1972;74⬊142–144. B, From Kielar RA, Cunningham GC, Gerson KL. Occurrence of herpes zoster
ophthalmicus in a child with absent immunoglobulin A and deficiency of delayed hypersensitivity. Am J Ophthalmol 1971;
72⬊555–556.)

begins with fever, malaise, headache, and pain or a burning
dysesthesia in the cutaneous distribution of one or more
branches of the trigeminal nerve. The skin in the affected
region may be hypersensitive to touch. A typical rash then
develops within 24 hours to a few days later. Ocular involve-
ment usually develops a few days after the rash, but it occa-
sionally occurs concomitant with the rash and, rarely, may
precede it by 1–2 days.
The quality and duration of the pain associated with acute
HZO is variable. In contrast to the pain of trigeminal neural-
gia, which is intermittent and lancinating, the pain of HZO
is steady and sustained. It is burning, aching, and nonthrob-
bing, and it usually diminishes gradually in intensity. It may
be experienced in any part of the distribution of the trigemi-
nal nerve, but it most often affects the forehead. It usually
regresses spontaneously within 2–3 weeks; however, it may
persist and become postherpetic neuralgia, or it may resolve
completely, only to be followed days to weeks later by post-
herpetic neuralgia.
The rash of HZO is identical with that which occurs on
other parts of the body (446,489,490). It initially is maculo-
papular but soon becomes vesicular, with erythema, edema,
and induration at the base of some of the vesicles (Fig.
57.22). Most of the vesicles contain turbid, yellow fluid, but
some contain blood. When the rash affects the eyelids, it
commonly produces swelling and ptosis related to mechani-
cal factors, such as inflammation and edema. The vesicles
and associated swelling and inflammation gradually resolve
over several weeks, but the deep dermal involvement can
lead to permanent scarring of the forehead and scalp, and
scarring of the eyelids may cause entropion, ectropion, and
trichiasis (489) (Fig. 57.23). Rarely, ischemic changes cause
sloughing of the eyelids (490). Permanent loss of eyelashes,
epicanthal lesions, and nonneurogenic ptosis can also occur.
Ocular complications are common in patients with HZO
(482). The incidence of these complications is greatest in
patients older than 50 years and in those with Hutchinson’s
sign (492). Patients with HIV infection or AIDS are at an
especially high risk for significant visual loss, particularly
if treatment is delayed (493).
Patients with HZO often develop a follicular conjunctivi-
tis that may be associated with petechial hemorrhages
(446,477). Vesicular eruptions on the conjunctiva may also
occur, and VZV virus DNA may be detected by PCR and
restriction enzyme analysis in the conjunctiva of these pa-
tients (494).
Patients with HZO in whom the inflammation affects the
lacrimal drainage system may develop scarring and obstruc-
tion leading to chronic epiphora that persists long after the
active inflammation ceases. The sclera also may be affected
 VIRUSES (EXCEPT RETROVIRUSES) AND VIRAL DISEASES 3153

Figure 57.23. Severe scarring of the face after an attack of herpes zoster ophthalmicus in a 75-year-old man. A, Frontal view.
B, Side view.

during an attack of HZO (446). Scleritis usually develops cein and rose bengal. VZV may be cultured from these le-
during the acute phase of the disease, but it can also occur sions, and PCR demonstrates VZV DNA in the lesions (477).
2–3 months after the vesicles disappear (478,495). The scle- About 4% of patients with HZO develop corneal epithelial
ritis may be diffuse or nodular. It usually is anterior and is lesions consisting of sharply demarcated, white to gray
characterized histopathologically by accumulations of lym- plaques of variable size and shape. This condition, called
phocytes and plasma cells. Occasionally, however, posterior mucous plaque keratitis, may be associated with the develop-
scleritis occurs in the setting of HZO. In this setting, the ment of cataract, increased intraocular pressure, iritis, infil-
inflammation may also involve the perineural and perivascu- tration of corneal stroma, and subsequent corneal ulceration
lar tissue behind the eye. Chronic scleritis may cause pro- (446). Patients with AIDS (with or without a history of HZO)
gressive thinning of the sclera with secondary staphyloma may develop a chronic VZV epithelial keratitis characterized
or even perforation (496). Rare patients with HZO develop
episcleritis rather than scleritis (495). The episcleritis usually
is characterized by nongranulomatous infiltration with lym-
phocytes and plasma cells (496). It resolves spontaneously
in a short period of time, but it persists for more than 3
months in a significant percentage of patients (497).
Corneal damage is common in patients with HZO and can
occur early or late in the course of the disease. A variety of
disturbances can affect the corneal epithelium, stroma, or
both (446,491,495). A mild punctate epithelial keratitis oc-
curs in about 50% of patients with HZO (489,498). The
process is associated with irritation and tearing of the af-
fected eye and, in some cases, with mild blurred vision or
monocular diplopia. Other patients develop dendritiform
(pseudodendritic) lesions that are different from those
caused by herpes simplex in that they have blunt, rather than Figure 57.24. Dendritiform (pseudodendritic) keratitis in herpes zoster
pointed, ends (Fig. 57.24). These lesions are also located ophthalmicus. Note thickened, coarse-appearing lesions with blunted ends.
more superficially and peripherally than are the dendrites of (From Piebenga LW, Laibson PR. Dendritic lesions in herpes zoster oph-
herpes simplex, and they stain minimally with both fluores- thalmicus. Arch Ophthalmol 1973;90⬊268–270.)
3154 CLINICAL NEURO-OPHTHALMOLOGY

by dendritiform lesions, a prolonged course, and frequently
extreme pain (499).
Many patients with HZO who develop corneal epithelial
defects, particularly patients with punctate epithelial keratitis
and pseudodendrites, also develop infiltration of the anterior
corneal stroma (480,498). The stromal disease is commonly
located just beneath the epithelial disease and usually devel-
ops within the first 3 weeks of the onset of the acute infec-
tion. About 10% of patients with infiltration of the corneal
stroma in the setting of HZO develop disciform stromal kera-
titis characterized by a localized area of deep corneal edema
with folds in Descemet’s membrane (489). This condition,
which usually occurs about 3–4 months after the onset of
initial symptoms and signs, is associated with an intact cor-
neal epithelium. Anterior uveitis may be present, however,
and persistent nongranulomatous or granulomatous inflam-
mation of the stroma may produce deep corneal neovascu-
larization, scarring, and fibrosis leading to permanent visual
loss (496,497). Attempts at corneal transplantation in such
patients often fail, at least in part because of chronic inflam-
mation in the corneal bed of the host. VZV DNA can be
detected by PCR in the corneas of patients with this condi-
tion (500,501).
One of the most severe corneal disturbances that can de-
velop in patients with HZO is neurotrophic keratitis (446).
This condition, which occurs in the setting of loss of corneal
sensation, is characterized by recurrent breakdown of cor-
neal epithelium. It may lead to corneal ulceration and ulti-
mately to perforation of the cornea (491,498).
Most corneal disturbances caused by HZO resolve within
about 1 year; however, some patients have permanent visual
loss from corneal scarring, and others experience episodes
of recurrent epithelial breakdown and intermittent ulceration
that may result in part from the permanent eyelid scarring,
cicatricial ectropion, trichiasis, entropion, or eyelid margin
deformities that so often accompany this disease. Such pa-
tients are also at increased risk for developing secondary
bacterial infections of the cornea. About 10–20% of patients
have persistent reduced corneal sensation that usually is
highly localized (497,498).
Patients who develop inflammation of the cornea, sclera,
or both in the setting of HZO also are likely to develop
anterior uveitis (iritis) (480,491,495,502,503). Even patients
without overt inflammation affecting the cornea or sclera
may develop anterior uveitis during the acute phase of the
disease or several weeks to months after the disappearance
of the rash. The uveitis associated with HZO usually is
characterized by eye pain, photophobia, blurred vision,
redness of the eye in the typical pattern called ‘‘ciliary
flush,’’ miosis, a mild to moderate anterior chamber reac-
tion, and keratic precipitates. Both anterior and posterior
synechiae commonly occur in such patients, and rare pa-
tients develop hyphema and hemorrhagic glaucoma (487).
Atrophy of the iris often occurs in patients with anterior
uveitis associated with HZO (Fig. 57.25). It may be sectoral
or diffuse and is caused by ischemic necrosis of the iris
secondary to vasculitis.
The iritis associated with HZO usually is self-limited, re-
solving within a few months, but some cases last for 1 year
or longer. Such cases may be associated with the develop-
ment of cataract, glaucoma, and even anterior segment is-
chemia with necrosis progressing to phthisis bulbi (504).
The intraocular pressure may be elevated or low in pa-
tients with HZO, depending on the effects of inflammation

Figure 57.25. Iris atrophy after uveitis in a patient with herpes zoster ophthalmicus. A, Drawing of combined iris stromal
and sphincter atrophy. B, Iris angiogram shows sectoral avascular regions of iris, indicating sites of atrophy. Note lack of
vascular filling from 2 to 4 o’clock and dilation of neighboring radial vessels. (From Marsh RJ, Easty DL, Jones BR. Iritis
and iris atrophy in herpes zoster ophthalmicus. Am J Ophthalmol 1974;78⬊255–261.)
 VIRUSES (EXCEPT RETROVIRUSES) AND VIRAL DISEASES 3155

on the production and outflow of aqueous humor. Intraocular
inflammation often decreases the production of aqueous
humor, but it may also cause a variety of defects that result
in obstruction of normal pathways of outflow of the fluid
and secondary glaucoma (497,503). The intraocular pressure
often returns to normal as the uveitis resolves; however,
when the pressure remains elevated, the patient may develop
characteristic glaucomatous visual field changes associated
with progressive cupping of the optic disc (491). The second-
ary glaucoma that occurs in patients with HZO may have
a variety of causes, including obstruction of the trabecular
meshwork by debris and cells, rubeosis iridis or anterior
synechiae that occlude the anterior chamber angle, or poste-
rior synechiae leading to pupillary block. A combination of
these mechanisms is responsible for increased intraocular
pressure in some patients.
Retinal complications can occur in patients with HZO and
may be caused by vasculitis, direct inflammation of tissue,
or both (443,478,480,495). Such complications seem to be
more common in patients with AIDS. Ischemic retinal dis-
turbances are caused by vasculitis and include multifocal
areas of perivasculitis, central retinal vein occlusion, central
retinal artery occlusion, branch retinal artery occlusion,
branch retinal vein occlusion, ischemic retinopathy, or a
combination of these manifestations (505,505a). Severe reti-
nal ischemia may lead to complete or incomplete retinal
detachment.
Roberts et al. (506) described two patients who, several
months after attacks of acute HZO, developed unilateral pos-
terior fundus features of yellow, nonpigmented, punched-
out areas of retinal pigment epithelial and choroidal pigment
atrophy, termed herpes zoster chorioretinopathy. An occlu-
sive vasculitic process was proposed as the pathogenesis for
this disorder.
Margolis et al. (480) reported a severe retinitis primarily
affecting the outer layers of the retina, unassociated with
uveitis, and with little or no clinical evidence of retinal vas-
culitis in five patients with AIDS, two of whom had HZO.
The condition was bilateral in three patients and unilateral
in two. All five patients experienced progression of the dis-
ease and were left with atrophic and necrotic retinas, pale
optic discs, and narrowed retinal vessels (Fig. 57.26). The
retinitis was thought by the authors to have been caused by
VZV infection in all five patients for several reasons. First,
the onset of the retinitis in four of the five patients either
followed or was coincident with an eruption of dermatomal
herpes zoster. Second, VZV was cultured from chorioretinal
specimens obtained from two patients, and VZV antigen was
detected in a vitreal aspirate from a third patient. Third, VZV
antigen was detected, using immunocytochemistry, in the
outer retina of two eyes that were enucleated. Finally, viral
capsids with the size and shape of herpesviruses were identi-
fied in the outer retina of two enucleated eyes, using electron
microscopy. Other authors subsequently reported additional
cases of this form of retinitis, which is called progressive
outer retinal necrosis to distinguish it from ARN (480,507).
As noted earlier, the ARN syndrome is caused in many
cases by herpesvirus infection of the eye, with HSV and
VZV being the viruses most often implicated. Most cases
of VZV-associated ARN occur in patients with no previous
history or concurrent evidence of VZV infection (508) or in
patients who recently experienced an attack of herpes zoster

Figure 57.26. Progressive outer retinal necrosis (PORN) unassociated with retinal vasculitis in herpes zoster ophthalmicus
associated with AIDS. The patient was a 45-year-old man who was thought to be healthy until he developed right-sided herpes
zoster ophthalmicus associated with a severe keratouveitis in the right eye. An evaluation revealed evidence of infection with
HIV. The skin lesions cleared, but the right eye developed severe glaucoma and eventually became blind. Six months later,
the patient developed progressive loss of vision in the left eye. Visual acuity was 20/50 in the eye. A, Ophthalmoscopic
appearance of the left ocular fundus at onset of visual symptoms in that eye. There is opacification of the entire retina. A few
retinal hemorrhages are seen. B, Appearance of left ocular fundus 6 days later. The retinal vessels are becoming narrowed,
and more retinal hemorrhages have developed. (Figure continues.)
3156 CLINICAL NEURO-OPHTHALMOLOGY

Figure 57.26. Continued. C, Appearance of left ocular fundus 10 days after onset of visual symptoms. The optic disc has
become pale, and the retinal arteries have become further attenuated. The retinal edema is resolving, as are the retinal hemor-
rhages. D, Appearance of left ocular fundus 4 months after onset of visual symptoms. The optic disc is markedly pale; the
retinal arteries are narrowed in some areas and completely occluded in others; and the retina is atrophic. Resolving hemorrhages
are present. (From Margolis TP, Lowder CY, Holland GN, et al. Varicella-zoster virus retinitis in patients with the acquired
immunodeficiency syndrome. Am J Ophthalmol 1991;112⬊119–131.)

affecting the thoracic or lumbar dermatomes. However,
some cases of ARN occur after or concurrent with HZO
(213,509,510) (Fig. 57.27). ARN also may occur in the eye
contralateral to that affected by HZO (511,512).
Ischemic and inflammatory damage to the uveal tract may
cause visual loss in patients with HZO. Choroidal involve-
ment usually is diffuse and may be associated with posterior
uveitis (513–515) (Fig. 57.28). Pathologic examination in
such patients shows changes that range from a nongranulo-
matous infiltration of the iris, ciliary body, and choroid with

Figure 57.27. Acute retinal necrosis in herpes zoster ophthalmicus

(HZO). The patient was a 43-year-old woman who developed right-sided
HZO. Five days later, she noted decreased vision in the right eye. Visual
acuity was 20/30 OD and 20/20 OS. There was a mild vitritis. The right
optic disc is hyperemic and swollen. The right macula was edematous, and
areas of retinitis were seen in the periphery of the right ocular fundus.
(From Browning DJ, Blumenkranz MS, Culbertson WW, et al. Association
of varicella zoster dermatitis with acute retinal necrosis syndrome. Ophthal-
mology 1987;94⬊602–606.)
Figure 57.28. Multifocal choroiditis associated with herpes zoster oph-
thalmicus (HZO). The patient was a 67-year-old man who developed left-
sided HZO associated with persistent uveitis and decreased vision in the
left eye. Visual acuity was 20/25 OD and 20/70 OS. The left ocular fundus
shows multiple pale yellow areas affecting the choroid and retinal pigment
epithelium. (From Bloom SM, Snady-McCoy L. Multifocal choroiditis uve-
itis occurring after herpes zoster ophthalmicus. Am J Ophthalmol 1989;
108⬊733–735.)
 VIRUSES (EXCEPT RETROVIRUSES) AND VIRAL DISEASES 3157

PMNs, lymphocytes, and plasma cells in patients with acute
inflammation to a severe granulomatous inflammation
throughout the uveal tract with secondary retinal damage
in patients with chronic disease (494,495). Inflammation of
posterior ciliary arteries and nerves, which also may be mild
or severe, is present in some cases and may be associated
with evidence of optic neuropathy.
Perhaps the most devastating complication of HZO is
acute phthisis bulbi (504). This condition, which occurs in
less than 1% of patients with HZO, results from ischemic
necrosis of the ciliary body, caused by severe occlusive vas-
culitis.
Both herpes zoster and HZO may be complicated by cra-
nial neuropathies other than trigeminal neuropathy. The
most common are ocular motor nerve pareses and optic neu-
ropathy.
The ocular motor nerves may be damaged, singly or in
combination, in patients with herpes zoster, producing var-
ious degrees of ophthalmoparesis (504,516–519). Although
some patients with nonophthalmic herpes zoster develop sin-
gle or multiple ocular motor nerve pareses (520), such pare-
ses occur most often in patients with either herpes zoster
oticus or HZO (521). Most ocular motor nerve pareses that
complicate HZO, herpes zoster oticus, and nonophthalmic
zoster develop 1–2 weeks after the onset of the rash. When
an ocular motor nerve paresis occurs after a longer interval,
the patient should be evaluated for some other underlying
cause, such as an intracranial tumor (522). Even ocular motor
nerve pareses that seem to accompany an attack of HZO
may be caused by some other process.
The majority of ocular motor nerve pareses that develop
in patients with HZO occur on the side of the cutaneous
eruption, but some occur on the contralateral side, and some
are bilateral. Most patients develop combinations of ocular
motor nerve pareses that may be mild (518) or so severe
that the patient has complete ophthalmoplegia of the affected
eye associated with varying degrees of proptosis and optic
neuropathy (i.e., an orbital apex or cavernous sinus syn-
drome) (448,504,519,521,523,524). Many cases of HZO,
however, are characterized by the development of an isolated
ocular motor nerve paresis (518). Either isolated abducens
(525) or trochlear (517,526,527) nerve paresis can occur
(Fig. 57.29), but the oculomotor nerve is affected most often
(446,521,526). The oculomotor nerve paresis that occurs in
patients with HZO may be complete or incomplete, but there
is almost always some degree of ptosis, and the pupil is often
affected (518) (Fig. 57.30).
Marsh et al. (521) found that there was a highly significant
association (P ⬍ 0.001) between ocular motor nerve pareses
and uveitis and iris atrophy in patients with HZO. Thus,

Figure 57.29. Isolated trochlear nerve paresis in a patient with herpes zoster ophthalmicus (HZO). The patient was a 63-
year-old woman who developed left-sided HZO associated with a severe iridocyclitis. One month later, she developed vertical
diplopia. Ocular movements show marked left hypertropia in primary position with underaction of the left superior oblique
muscle on gaze down and right and overaction of the left inferior oblique muscle on gaze right and on gaze up and right. Note
resolving skin lesions on left forehead. The left pupil is dilated from atropine. (From Scharf J, Meyer E, Zonis S. Trochlear
nerve palsy in a case of herpes zoster ophthalmicus. Ann Ophthalmol 1979;11⬊568–570.)
3158 CLINICAL NEURO-OPHTHALMOLOGY
Figure 57.30. Isolated oculomotor nerve paresis in herpes zoster ophthal-
micus (HZO). A, Complete right-sided ptosis from an isolated oculomotor
nerve palsy in a 78-year-old woman with ipsilateral HZO. The patient was
also blind in the right eye from a central retinal artery occlusion. B, Com-
plete left oculomotor nerve paresis in a 64-year-old man with ipsilateral
HZO. The patient is looking to the left. Note complete lack of adduction
of the left eye. Also note a dilated left pupil. (From Pierce LE, Jenkins RB.
Herpes zoster ophthalmicus treated with cytarabine. Arch Ophthalmol 1973;
89⬊21–24.)
patients in whom an oculomotor nerve paresis occurs in the
setting of HZO, whether in isolation or in combination with
other ocular motor nerve pareses, must be followed closely
to make certain that they do not develop intraocular compli-
cations of HZO that are not identified because of the ipsi-
lateral ptosis. We examined a woman in whom this compli-
cation occurred. The patient was a 69-year-old woman who
developed severe, right-sided HZO that was complicated by
complete ophthalmoplegia of the right eye. When she was
first examined 3 weeks after the onset of symptoms, she had
normal best-corrected visual acuity in the right eye, but she
had complete oculomotor, trochlear, and abducens nerve pa-
reses (Fig. 57.31). Several weeks later, although she had
noted no change in her visual status because of a complete
ptosis, she now had hand motions vision in the right eye,
severe disciform keratitis, and a severe anterior uveitis with
formation of both anterior and posterior synechiae. She even-
tually lost all vision in the eye.
The ocular motor nerve pareses that occur in patients with
HZO or nonophthalmic zoster usually are self-limited unless
associated with a meningoencephalitis (528) or meningora-
diculitis (529). Most patients, particularly those with abdu-
cens or trochlear nerve paresis, but even those with total
ophthalmoplegia, experience complete or near-complete res-
olution within 3–6 months (526,529) (Fig. 57.32). However,
we and others have seen patients in whom an oculomotor
nerve paresis resolved slowly and incompletely over 1 year
or longer (526,529). In addition, rare patients with zoster-
associated oculomotor nerve pareses develop secondary ab-
errant regeneration of the oculomotor nerve that may or may
not be visually disabling. We saw such a patient, a 47-year-
old woman who developed right-sided HZO complicated
by a cavernous sinus syndrome characterized by ipsilateral
oculomotor, trochlear, and abducens nerve pareses and a
trigeminal sensory neuropathy. The condition eventually re-
solved, leaving the patient with evidence of secondary oculo-
motor nerve synkinesis.
The pathogenesis of the ocular motor nerve pareses that
develop in patients with HZO is controversial. Hedges and
Albert (496) described ‘‘demyelination and inflammation’’
of the ocular motor nerves in the cavernous sinus of two
patients who had HZO with ophthalmoparesis, but they did
not provide detailed descriptions and illustrations of the pa-
thology. Lavin et al. (447) reported the complete pathology
in a case of HZO complicated by complete ipsilateral troch-
lear, abducens, and oculomotor nerve pareses with pupillary
involvement. The patient was a 57-year-old woman with
diabetes mellitus controlled by diet alone who subsequently
developed a contralateral hemiparesis. She died about 2
months after the onset of the HZO and about 2–3 weeks after
the onset of the ophthalmoplegia. Postmortem examination
revealed normal oculomotor, trochlear, and abducens nuclei,
although the number of neurons in the right main sensory
nucleus of the trigeminal nerve was decreased. The right
gasserian ganglion showed calcification, monocytic infil-
trates, cell loss, demyelination, degeneration of axons, and
evidence of vasculitis with infiltration of the adventitia of
affected vessels by lymphocytes and histiocytes. Occasional
inflammatory cells were present throughout the vessel wall,
and there was disruption of the internal elastic lamina. The
tract of the right trigeminal nerve nucleus showed demyelin-
ation, proliferation of both astrocytes and microglial cells,
and infiltration by monocytes. The oculomotor, trochlear,
and abducens nerves within the right cavernous sinus were
demyelinated and contained monocytic infiltrates, and sev-
eral of the vessels supplying these nerves showed intimal
proliferation and perivascular monocytic infiltrates. Al-
though the extraocular muscles were not studied, the find-
ings of Lavin et al. (447) suggest that the ophthalmoplegia
in this patient was caused by damage in the peripheral por-
tion of the ocular motor nerves, perhaps from local spread
VIRUSES (EXCEPT RETROVIRUSES) AND VIRAL DISEASES 3159

Figure 57.31. Generalized ophthalmoplegia from combined ocular motor nerve palsies
in a 69-year-old woman with herpes zoster ophthalmicus. The patient has left-sided oculo-
motor, trochlear, and abducens nerve palsies. A, External appearance of patient. Note com-
plete left ptosis and lesions on tip and left side of nose. B, Close-up of patient. C, Appearance
of eyes with left eyelid manually elevated and patient fixing straight ahead. Note abducted
and depressed position of left eye. Left pupil is dilated. D, Attempted right gaze. The left
eye does not adduct. E, Attempted left gaze. The left eye does not abduct. F, Attempted
upgaze. The left eye does not elevate. G, Attempted downgaze. The left eye does not
depress.
3160 CLINICAL NEURO-OPHTHALMOLOGY

Figure 57.32. Recovery of eye movement after ophthalmoplegia caused by herpes zoster ophthalmicus (HZO). The patient
was a 70-year-old man who developed ophthalmoplegia and ptosis 10 days after the onset of left-sided HZO. A, The patient
has a complete left-sided ptosis. He also has right-sided ptosis caused by age-related dehiscence of the levator palpebrae
superioris muscle. B, When the patient fixates with the right eye, the left eye is slightly exotropic. C, On attempted right gaze,
the left eye adducts only to the midline. D, On attempted left gaze, the left eye shows mild limitation of abduction. E, Twelve
weeks later, the left-sided ptosis has resolved, and the left eye no longer is exotropic. Note persistent right-sided ptosis from
levator dehiscence. F, On attempted right gaze, the left eye adducts almost completely. G, On attempted left gaze, the left eye
abducts completely. (From Archambault P, Wise JS, Rosen J, et al. Herpes zoster ophthalmoplegia: report of six cases. J Clin
Neuroophthalmol 1988;8:185–191.)

of VZV, inflammation, or both from the adjacent trigeminal
nerves.
A case reported by Pierce and Jenkins (530) may shed
some light on the location of the lesions causing ocular motor
nerve pareses in HZO. These authors described a 64-year-old
man who developed left-sided HZO that was complicated
by the development of complete ipsilateral oculomotor and
trochlear nerve pareses. There was complete left ptosis and
a dilated nonreactive left pupil. The patient eventually re-
covered, and his ocular motility and alignment returned to
 VIRUSES (EXCEPT RETROVIRUSES) AND VIRAL DISEASES 3161

normal, but the left pupil remained dilated and nonreactive
to light. Two years after the initial infection, the left pupil
had become smaller than the right. It barely reacted to light
stimulation, but it reacted briskly during near viewing, and
it constricted after instillation of 2.5% methacholine chloride
(Mecholyl). The characteristics of this pupil suggest a pe-
ripheral oculomotor nerve lesion. Although we are aware
that lesions of the oculomotor nerve proximal to the ciliary
ganglion can result in apparent denervation supersensitivity
to both methacholine and pilocarpine, we believe that in this
patient the lesion was located in the orbit, affecting both pre-
and postganglionic oculomotor nerve fibers and allowing
the bulk of the oculomotor nerve paresis to resolve, while
maintaining a complete tonic pupil.
Kawasaki and Borruat (531) described acute orbital myo-
sitis preceding HZO. The patient was a 47-year-old woman
who developed acute eye pain and diplopia preceding the
vesicular rash of HZO. MR imaging showed enlargement
and enhancement of the extraocular muscles consistent with
an inflammatory myopathy. Following oral acyclovir and
prednisone therapy, all the manifestations resolved.
Patients with herpes zoster may develop an optic neuropa-
thy that may be mild or severe. Like the ocular motor nerve
pareses that occur in patients with herpes zoster, zoster-re-
lated optic neuropathy tends to occur more often in patients
with HZO than in patients with nonophthalmic zoster
(496,517,532–542). The optic neuropathy is almost always
unilateral, although bilateral cases occur (517,536). Whether
unilateral or bilateral, herpes zoster-related optic neuropathy
usually begins 1–4 weeks after the onset of the rash, al-
though it may develop months later (517). Persons of all
ages may be affected. The optic neuropathy may occur in
isolation, in association with a single ocular motor nerve
paresis, or in association with multiple ocular motor nerve
pareses (448,517). In patients with AIDS, retrobulbar optic
neuritis may precede the development of ARN (539,540).
In one case of optic neuropathy associated with herpes zos-
ter, there was simultaneous involvement of the retina, optic
chiasm, and optic nerve, characterized in part by a bitem-
poral visual field defect (542). Visual acuity usually declines
significantly in patients with herpes zoster optic neuropathy
and may be reduced to no light perception. The optic disc
may be normal or swollen; in the latter setting, there may
be an associated macular star figure composed of lipid, pro-
ducing the clinical picture of a neuroretinitis (538,543). Vis-
ual recovery is variable, but almost all patients have signifi-
cant and permanent reduction in vision in the affected eye,
a persistent RAPD, and pallor of the affected optic disc.
The pathogenesis of HZO-related optic neuropathy is
probably multifactorial (496). Patients examined histopatho-
logically show severe granulomatous inflammation of the
optic nerve that may extend to the optic chiasm and optic
tracts. Thus, at least some cases of optic neuropathy that
occur in the setting of HZO are examples of optic neuritis
(Figs. 57.33 and 57.34). This pathologic observation is con-
sistent with the clinical manifestations of the optic neuropa-
thy in some patients (536,544).
Some optic neuropathies associated with HZO are caused
by inflammatory thrombosis of the posterior ciliary arteries
and thus are examples of arteritic ischemic optic neuropathy
(545,546) (Fig. 57.35). Scharf et al. (547) and Atmaca and
Ozmert (548) reported cases of combined anterior ischemic
optic neuropathy and central retinal artery occlusion that
occurred in the setting of HZO, presumably the result of

Figure 57.33. Presumed anterior optic neuritis associated with herpes zoster ophthalmicus (HZO). The patient was a 40-
year-old woman with known HIV infection who developed right-sided HZO. Three weeks later, she developed left-sided HZO
and simultaneously noted decreased vision in the left eye. Visual acuity was 20/40 OD and light perception OS. There was a
left relative afferent pupillary defect. A, The left optic disc is markedly swollen, the retinal veins are somewhat dilated, and
there are peripapillary hemorrhages and exudates. B, Axial CT scan after intravenous injection of contrast material shows a
diffusely enlarged left optic nerve. (From Litoff D, Catalano RA. Herpes zoster optic neuritis in human immunodeficiency
virus infection. Arch Ophthalmol 1990;108⬊782–783.)
3162 CLINICAL NEURO-OPHTHALMOLOGY

Figure 57.34. Presumed retrobulbar optic neuritis associated with herpes zoster ophthalmicus (HZO). The patient was a 19-
year-old man who developed left-sided HZO. Three weeks later, he developed decreased vision in the left eye. Visual acuity
was 20/20 OD and no light perception OS. The left pupil was amaurotic. A, The left optic disc has a normal appearance. The
patient was treated with prednisone. Two months later, visual acuity had improved in the left eye to counting fingers at 2 feet.
B, The left optic disc is now pale. (From Tunis SW, Tabert MJ. Acute retrobulbar neuritis complicating herpes zoster ophthal-
micus. Ann Ophthalmol 1987;19⬊453–460.)

vasculitis affecting either both the posterior ciliary vessels
and the central retinal artery or perhaps just the ophthalmic
artery.
A pathologically proven case of retrobulbar ischemic
optic neuropathy in the setting of HZO was reported by Lexa
et al. (448). The patient was a 41-year-old woman with scle-
roderma who developed right HZO. About 2 weeks later,
she developed acute loss of vision in the right eye and then
became encephalopathic. An examination at that time re-
vealed that the patient had no perception of light with the

Figure 57.35. Presumed anterior ischemic optic neuropathy associated with herpes zoster ophthalmicus (HZO). The patient
was a 56-year-old man with a history of a previous attack of right-sided HZO who developed an attack of left-sided HZO
associated with anterior uveitis. About 4 weeks after the onset of symptoms, the patient experienced acute painless loss of
vision in the left eye. Visual acuity was 20/15 OD and 20/200 OS. A, Visual field of left eye determined by kinetic perimetry
shows an absolute inferior arcuate defect. B, The left optic disc is swollen and hyperemic. Note dilation of small capillaries
on disc surface and peripapillary hemorrhage inferior to the disc. (From Borruat FX, Herbort CP. Herpes zoster ophthalmicus:
anterior ischemic optic neuropathy and acyclovir. J Clin Neuroophthalmol 1992;12⬊37–40.)
 VIRUSES (EXCEPT RETROVIRUSES) AND VIRAL DISEASES 3163

right eye, which was chemotic, proptotic, and completely

paretic. The right pupil was dilated and nonreactive to both
direct and consensual light stimulation. The right ocular fun-
dus appeared normal, except for a few cotton-wool spots. A
few cotton-wool spots were also seen in the fundus of the
left eye, which was otherwise normal. MR imaging showed
changes consistent with extensive inflammation in the right
orbit, abnormal meningeal enhancement, and changes con-
sistent with infarction in the right pons. Despite aggressive
supportive and antiviral therapy, the patient died 4 weeks
after the onset of symptoms. Postmortem examination re-
vealed herpetic dermatitis in the distribution of the first divi-
sion of the trigeminal nerve. Microscopic examination of
the leptomeninges showed granulomatous angiitis, with an
inflammatory infiltrate consisting of epithelioid cells, lym-
phocytes, and plasma cells in the adventitia of blood vessels.
Segmental vasculitis affected the large arteries of the anterior
circulation and the distal middle cerebral arteries bilaterally.
Several scattered areas of infarction were seen in the pons
and medulla. The right optic nerve showed an extensive peri-
axial infarct with minimal evidence of inflammation.
Lower cranial neuropathies are rare complications of
herpes zoster (369). Patients in whom such neuropathies
occur may develop a variety of manifestations, including
vesicles on one side of the pharynx, larynx, and tongue;
weakness of the muscles of these structures; vomiting; hic-
cough; and glossopharyngeal neuralgia (549). Kahane et al. Figure 57.36. Tonic pupil in herpes zoster ophthalmicus (HZO). The
(550) described a 70-year-old man who developed aseptic patient was a 54-year-old man who developed right-sided HZO. He initially
meningitis associated with a palatolaryngeal herpetic erup- had a dilated right pupil, but the pupil eventually became small and poorly
tion, a jugular foramen syndrome affecting the glossopha- reactive. A, When the patient fixates on a distant target, the right pupil is
ryngeal, vagus, and spinal accessory nerves, and a high level smaller than the left. The right pupil is also slightly irregular. B, When
of serum antibody to VZV. Hayashi et al. (551) also reported light is shined in the right eye, the right pupil does not react, but the left
pupil reacts normally. C, When light is shined in the left eye, the left
a jugular foramen syndrome in a patient without a typical
pupil constricts, but the right pupil does not react consensually. D, During
cutaneous rash but with elevated IgM and IgG antibodies to accommodation, both pupils constrict; however, constriction of the right
VZV in the serum and CSF. Ohashi et al. (552) described pupil was slow, and there was slow redilation after constriction. (From
a 31-year-old woman with dysphagia, hoarseness, poor ele- Naquin HA. Argyll Robertson pupil following herpes zoster ophthalmicus:
vation of the palate on the right, and VZV vesicles on the with remarks on the efferent pupillary pathways. Am J Ophthalmol 1954;
right concha within the wall of the external auditory meatus. 38⬊23–33.)
Thus, the patient had isolated involvement of the vagus nerve
by VZV with the eruption in the distribution of the auricular
branch of the vagus (Arnold’s nerve) in the ear. Osaki et al. of HZO, at which time the pupil becomes widely dilated and
(553) described a case of zoster-related polyneuritis cranialis nonreactive to both light and near stimulation. If the cornea
affecting the right glossopharyngeal, vagus, and spinal ac- is not affected and if there is no evidence of intraocular
cessory nerves. Interestingly, this patient never had an her- inflammation or optic neuropathy, distance acuity is unaf-
petic rash (i.e., she had zoster sine herpete). fected, although near vision is reduced because of loss of
Abnormalities of pupillary function are common in pa- whatever accommodation the patient had before the disease
tients with HZO. Perhaps the most common finding is a began. Photophobia may be significant. The pupil initially
pupil that is damaged by intraocular inflammation. Such pu- is nonreactive to light, but it usually becomes somewhat
pils tend to be mid-dilated and poorly reactive. Severe vascu- reactive over time. As it does, it gradually becomes smaller
litis may produce ischemia of the iris, leading to sector iris and slightly irregular in size, and slit-lamp biomicroscopy
atrophy and a pupil that is poorly reactive or nonreactive to reveals areas of functioning iris sphincter separated by areas
both light and near stimulation. In other cases, the pupil is of paralysis. The ability of the pupillary sphincter to constrict
large and poorly reactive because of an oculomotor nerve during near viewing tends to recover faster than its reaction
paresis. to light, and this recovery usually is associated with some
In addition to the pupillary abnormalities described ear- return of accommodation; however, the constriction, al-
lier, herpes zoster may produce a tonic pupil (530,554,555) though better than the constriction to light, tends to be slow
(Fig. 57.36). The condition almost always occurs after an and somewhat irregular, and redilation of the pupil tends to
attack of HZO. The features are typical. The condition is be slow as well. A topical parasympathomimetic agent, such
almost always unilateral and occurs during the acute episode as 0.1% pilocarpine, produces marked pupillary constriction
3164 CLINICAL NEURO-OPHTHALMOLOGY
consistent with denervation supersensitivity of the iris
sphincter muscle, although it is unclear how long it takes
for denervation sensitivity to develop in this setting.
Although the unilateral disturbance of pupillary function
that occurs in herpes zoster (and particularly in HZO) is
sometimes called an ‘‘Argyll Robertson’’ or ‘‘Argyll Rob-
ertson-like’’ pupil (555), such pupils do not have typical
characteristics of Argyll Robertson pupils (i.e. normal con-
striction during near viewing and rapid redilation after con-
striction), and they are not caused by a lesion of the mesen-
cephalon but by inflammation and vasculitis affecting the
ciliary ganglion, short posterior ciliary nerves, or both.
Horner syndrome occasionally occurs in patients with
HZO (556) (Fig. 57.37), as it does in patients with zoster
that affects the maxillary and mandibular divisions of the
trigeminal nerve (476). The lesion is invariably ipsilateral
to the side of the HZO, but the exact site of the lesion is
unclear. It seems to us most likely that it is postganglionic
and that the sympathetic fibers are damaged from inflamma-
tion, vasculitis, or both. A patient described by Smith et al.
(556) developed a right abducens nerve paresis in addition
to a right postganglionic Horner syndrome, suggesting that
the site of the lesion was in the cavernous sinus.
Rare patients with herpes zoster develop an aseptic menin-
Figure 57.37. Horner syndrome associated with herpes zoster ophthal-
micus (HZO). The patient was a 53-year-old man who experienced an attack
of right-sided HZO complicated by the development of a right abducens
nerve paresis. No abnormalities of the pupil were noted at this time. A,
Appearance of the patient 4 weeks after the onset of signs and symptoms.
Note right-sided ptosis and miosis. Both pupils reacted normally to light
and near stimulation. There was still mild weakness of abduction of the
right eye. B, Appearance of the pupils 1 hour after topical instillation of
4% cocaine solution. The right pupil is unchanged in size; however, the
left pupil is dilated, indicating a Horner’s syndrome. (From Smith EF,
Santamarina L, Wolintz AH. Herpes zoster ophthalmicus as a cause of
Horner syndrome. J Clin Neuroophthalmol 1993;13⬊250–253.)
gitis (360,557–559). In some of these patients, the meningi-
tis occurs in the absence of any associated cutaneous lesions
(560). The meningitis of herpes zoster may resolve sponta-
neously, but most patients soon develop evidence of enceph-
alitis.
Encephalitis is also a rare complication of herpes zoster.
It occurs in less than 1% of all patients, although the risk
of developing it is increased in patients with AIDS, in immu-
nosuppressed patients with disseminated zoster, in bone mar-
row transplant patients, in elderly patients, and in patients
with zoster affecting the cranial nerves or the segments of the
cervical or upper thoracic cord (322,360,434,458,561–567).
Cheung et al. (568) described two patients with chronic renal
failure who were receiving dialysis when they developed
herpes zoster-associated encephalitis.
The clinical picture of herpes zoster encephalitis is ex-
tremely variable. There are no distinguishing diagnostic fea-
tures other than a zosteriform rash (241,369,458,569).
Symptoms usually begin about 9 days after the onset of the
rash, but they may develop as long as 6 weeks after the rash
first appears (570), begin simultaneously with the rash (571),
or even precede the rash by up to 30 days (572). Like aseptic
meningitis, zoster-related encephalitis and meningoencepha-
litis can occur in patients with no associated cutaneous erup-
tion (573,574).
The manifestations of zoster-related encephalitis usually
begin suddenly, but they may develop gradually. Most pa-
tients initially develop headaches, nuchal rigidity, and fever,
suggesting a meningitis (570,571,575). Soon, however, they
develop impairment of consciousness, visual hallucinations,
confusion, and delirium (568). Seizures and ataxia may also
occur (563,569). Segmental motor weakness may develop
(570), and some patients develop hemiparesis or choreoathe-
toid movements (571). Still other patients develop cranial
neuropathies. For example, Moulignier et al. (573) described
a patient with AIDS who developed zoster-related brain stem
encephalitis characterized by a right hemiparesis, a left Hor-
ner syndrome, a gaze-evoked bilateral horizontal nystagmus,
and a left abducens nerve paresis. Kondo et al. (576) de-
scribed a 64-year-old woman with zoster-related meningo-
encephalitis characterized in part by glossopharyngeal,
vagus, and spinal accessory neuropathies. MR imaging in
this patient revealed a lesion in the dorsal medulla. Papille-
dema may develop in patients with zoster-related encephali-
tis who have increased intracranial pressure (571).
Examination of the CSF in patients with herpes zoster
encephalitis typically shows a moderate but occasionally
marked elevation of pressure, a lymphocytic pleocytosis that
seldom is greater than 500 cells/mm3, an increased concen-
tration of protein, and a normal or low concentration of glu-
cose (322,568,569,571). VZV can be cultured from the CSF
in some cases (570,577). Interestingly, the CSF may be nor-
mal in some cases of herpes zoster encephalitis, and the CSF
findings do not seem to correlate with the clinical severity
of the disease. Diagnosis is confirmed by PCR analysis of
CSF levels of VZV DNA and assay of VZV antibody
(322,578,579).
Neuroimaging studies in patients with herpes zoster en-
cephalitis may be normal, may show a variety of nonspecific
changes in the gray and white matter (569), or may show
 VIRUSES (EXCEPT RETROVIRUSES) AND VIRAL DISEASES
lesions that initially involve the subcortical regions and are
nonenhancing but gradually coalesce to involve cortical
areas and become enhancing (563). The results of neuroim-
aging thus are useful primarily to eliminate other potential
causes of the clinical manifestations, such as tumor or stroke
(241).
The EEG may be normal or may show nonspecific abnor-
malities in patients with herpes zoster encephalitis. Diffuse
slow-wave activity that ranges from mild to severe and that
mirrors the clinical severity of the disease is often present
(568–571).
The duration of herpes zoster encephalitis is about 2
weeks. Factors that may increase the duration of active dis-
ease include immunosuppression and extracranial dissemi-
nated disease (570). The mortality rate varies from about
15–25% (570,580). As might be expected, patients who are
immunosuppressed or severely debilitated and patients with
disseminated zoster have the worst prognosis (368). Recov-
ery usually is complete in those who survive (298), but some
patients have persistent motor weakness, cranial neuropa-
thies, hemiparesis, psychosis, or a combination of these defi-
cits (570,571).
The most prominent pathologic features of herpes zoster
encephalitis are perivascular lymphocytic infiltration and
small hemorrhagic foci, particularly in subcortical structures
(570,571,581). Microglial proliferation may occur, destruc-
tion of neurons is an occasional finding, and areas of partial
demyelination may be present. Cerebral edema with hernia-
tion may be seen. Viral inclusions may be seen in glial cells,
neurons, and arteries of the brain (573,582), and VZV may
be cultured from CSF, brain, or both in such patients (577).
Gray et al. (564) described three AIDS patients with zos-
ter-related encephalitis in whom ventriculitis was a promi-
nent pathologic finding. In two patients, there was complete
acute or chronic necrosis of the ventricular wall with marked
vasculitis. In the third patient, the ependymal lining had an
irregular appearance, with foci of VZV-infected ependymal
cells, some of which protruded into the ventricular lumen.
Herpes zoster myelitis may occur by itself or in associa-
tion with signs and symptoms of encephalitis (i.e., encepha-
lomyelitis) (458,583–590). As is the case with pure zoster
encephalitis, the neurologic signs and symptoms of both my-
elitis and encephalomyelitis can develop concurrently with
the onset of the rash, but they usually follow it by a variable
period that ranges from several days to weeks, with a median
interval of about 10 days. Herpes zoster myelitis also may
occur several months before the appearance of skin lesions
(585) or without a cutaneous rash (587,588). The condition
may be acute, slowly progressive, or relapsing (583,584).
Weakness of the lower extremities, sensory disturbances,
and bladder dysfunction are all common. A complete
Brown-Séquard syndrome may occur.
Pathologic changes in the spinal cord in herpes zoster
myelitis and encephalomyelitis are similar to those seen in
the brain in pure encephalitis. They include perivascular in-
filtration with lymphocytes and plasma cells, microglial pro-
liferation, and hemorrhagic necrosis in affected segments
(369,520,564,581,583). Focal destruction of axons and areas
of demyelination may also be present (570,583).
3165
The duration of both herpes zoster myelitis and encephalo-
myelitis is, as with zoster encephalitis, about 2 weeks (583).
Factors that may increase the duration of active disease in-
clude immunosuppression and extracranial disseminated
disease (570). The mortality rate varies from about 15–25%
(570,580). As might be expected, patients who are immuno-
suppressed or severely debilitated and patients with dissemi-
nated zoster have the worst prognosis (369). Recovery usu-
ally is complete in those who survive (298), but some
patients have persistent motor weakness, neurogenic blad-
der, hemiparesis, or a combination of these deficits (570,
571,583).
The pathogenesis of herpes zoster meningitis, encephali-
tis, and myelitis is unclear. Not surprisingly, the two most
widely held views are that the syndrome is either the result
of direct viral invasion from the infected sensory ganglia
or the consequence of an immune-mediated, postinfectious
process analogous to that thought to occur in the encephalitis
that occurs after chickenpox. In favor of the direct viral inva-
sion theory are (a) the demonstration of Cowdry type A
inclusion bodies and particles consistent with VZV in glial
cells; (b) the isolation of VZV from the CSF, brain, and
spinal cord of some patients with zoster-related encephalitis
and myelitis; and (c) the demonstration of VZV-specific an-
tigens, antibodies against VZV, or both, in the CSF of such
patients. On the other hand, the frequently observed delay
of more than 1 week between the appearance of the zoster
rash and the onset of neurologic manifestations is consistent
with an immune-mediated process, and many of the patho-
logic changes seen in both zoster encephalitis and myelitis,
particularly perivenular demyelination and inflammation,
are also consistent with such a process. We suspect that both
mechanisms play a role in the development of these condi-
tions.
A polyradiculitis with the clinical features of Guillain-
Barré syndrome is a rare complication of herpes zoster
(561,586,591). Indeed, because both conditions are so com-
mon and because the combination of the two disorders is so
infrequently seen, it is conceivable that the association is
purely fortuitous, particularly when the two conditions occur
several months apart (369). Nevertheless, the well-docu-
mented association between chickenpox and the Guillain-
Barré syndrome (discussed previously) provides indirect
evidence that at least some cases of the syndrome that occur
within a few days to weeks after the onset of typical herpes
zoster are related to the underlying infection and are not a
fortuitous occurrence. The clinical features of Guillain-Barré
syndrome associated with herpes zoster are identical with
those of other cases of the Guillain-Barré syndrome. Like
Guillain-Barré syndrome that occurs in other settings, zoster-
associated Guillain-Barré syndrome may be fatal if the dis-
ease is not recognized and managed with supportive care
that consists of careful monitoring of autonomic functioning
(particularly with respect to cardiac arrhythmias) and as-
sisted respiration when needed. Recovery may be delayed
or incomplete in those who survive the illness. The patho-
genesis of zoster-associated Guillain-Barré syndrome is un-
known but may be an immune-mediated postinfectious
mechanism rather than direct virus invasion.
3166 CLINICAL NEURO-OPHTHALMOLOGY
A significant complication of both nonophthalmic herpes
zoster and HZO is ischemic stroke caused, in most cases,
by a granulomatous angiitis. The most common form of this
complication occurs after an otherwise uncomplicated attack
of HZO and consists of the delayed onset of a contralateral
hemiplegia caused by cerebral vasculitis (483,592–594).
The condition usually occurs in persons over 50 years of
age, some of whom have an underlying lymphoproliferative
disease (595). It may occur in childhood, however (594,596),
and it was even described in a 17-month-old boy whose
mother had an attack of chickenpox during the eighth month
of pregnancy (597).
Delayed cerebral vasculitis usually develops 3–7 weeks
after an episode of typical HZO, although it may develop
as long as 6 months after the rash has resolved (598,599).
Some affected patients have a necrotizing retinitis at the time
neurologic manifestations occur (593). The typical patient
suddenly develops a contralateral hemiparesis that may be
associated with aphasia, confusion, disorientation, distur-
bances of memory, or a combination of these. Just before
the hemiparesis occurs, some patients report blurred vision,
diplopia, or episodes of transient visual loss (600), and such
patients may be found to have an associated optic neuropa-
thy, one or more ocular motor nerve pareses, an homony-
mous visual field defect, or a combination of these manifes-
tations (447,592). The hemiparesis is slowly progressive,
rather than acute, in some patients (369).
Neuroimaging studies in patients with delayed cerebral
infarction after herpes zoster (especially HZO) usually show
changes consistent with an ischemic cerebral infarction
(447,600–602); however, Elble (603) described a patient in
whom CT scanning showed evidence of a hemorrhagic in-
farct, and Tomiyama et al. (604) described a patient in whom
neuroimaging revealed changes consistent with a subcortical
hemorrhage. Cerebral angiography typically shows ipsi-
lateral segmental narrowing of the internal carotid artery,
middle cerebral artery, anterior cerebral artery, or a combina-
tion of these vessels on the side opposite the hemiparesis
(ipsilateral to the HZO) (447,597,600,601) (Fig. 57.38), but
in some patients, angiography is entirely normal (605). In
some patients, MR angiography (MRA) or CT angiography
(CTA) demonstrates multiple focal stenoses involving the
proximal intracranial vessels corresponding to endarteritis
(606).
Laboratory studies in patients with zoster-related delayed
cerebral vasculitis reveal variable findings. For example, the
CSF may be normal, but it usually shows a mononuclear
pleocytosis of less than 100 cells/mm3 with a mild-to-moder-
ate increase in the protein concentration and a normal or low
concentration of glucose (369). The erythrocyte sedimenta-
tion rate (ESR) usually is normal, but it may be increased.
The diagnosis of delayed cerebral vasculitis associated
with HZO usually is suspected from the clinical setting. CT
scanning and MR imaging can be used to determine the
extent of the intracranial process. Conventional angiography
usually is used to confirm cerebral vasculitis, but MRA and
CTA often provide comparable results in such cases. In addi-
tion, Victor and Green (607) reported a case of delayed cere-
bral vasculitis after HZO, in which the diagnosis was estab-
lished by an ipsilateral temporal artery biopsy that revealed
evidence of a granulomatous arteritis.
The prognosis for recovery in patients who experience
herpes zoster-related delayed cerebral vasculitis is variable,
but most patients have a good outcome (241,597). The speed
and extent of recovery depend in part on the rapidity with
which the condition is correctly diagnosed and the aggres-
siveness with which the patient is monitored and supported.
Numerous pathologic studies of fatal cases of zoster-re-
lated delayed cerebral vasculitis reveal that it is caused by
a necrotizing granulomatous angiitis that affects small and
medium-sized meningeal and cerebral arteries. Giant cells
are often seen, and fibrinoid necrosis may be present
(298,600,602). Viral particles were demonstrated by electron
microscopy in sections of large intracranial arteries of a pa-
tient who developed this condition while being treated with
steroids (608).
Not all cases of delayed cerebral vasculitis associated with
herpes zoster cause an ischemic or hemorrhagic infarct.
O’Donohue and Enzmann (609) reported two cases in which
intracranial angiitis associated with HZO resulted in the de-
velopment of an intracranial aneurysm. In both patients, the
aneurysm eventually ruptured, causing both subarachnoid
and intraparenchymal hemorrhage.
Some cases of zoster-related delayed intracranial vasculi-
tis that occur after HZO affect areas of the brain other than
the territory of the ipsilateral middle cerebral artery, and
patients in whom this occurs may have neurologic deficits
other than, or in addition to, hemiparesis (607,610–615).
Neuro-ophthalmologic manifestations are common in these
patients. The patient described by Victor and Green (607)
had a contralateral homonymous hemianopia and a Horner
syndrome, in addition to a contralateral hemiparesis, associ-
ated with evidence of an occipital lobe infarction. Bourdette
et al. (612) also reported a case of HZO complicated by
delayed occipital infarction that caused a complete homony-
mous hemianopia, and Fryer et al. (613) described a patient
who developed an almost complete left homonymous hemia-
nopia and left-sided sensory neglect 8 weeks after an attack
of HZO and was found to have a right temporoparietal in-
farct. Patients who are immunosuppressed are particularly
likely to develop a diffuse angiitis with widespread involve-
ment of cerebral vessels after HZO (615).
Delayed intracranial infarction in the distribution of both
the internal carotid and the vertebrobasilar arterial distribu-
tions may occur not only after HZO but also after nonoph-
thalmic zoster (616). Ojeda et al. (617) described a pontine
infarction after an attack of cervical (C2) herpes zoster, and
several authors described similar cases (618–620) (Fig.
57.39). The patient described by Willeit and Schmutzhard
(618), for example, developed a Millard-Gubler syndrome,
characterized by a left abducens nerve paresis, a left facial
nerve paresis, and a right hemiparesis, 6 weeks after other-
wise uncomplicated herpes zoster affecting the C2 and C3
dermatomes. The patient subsequently progressed to a com-
plete locked-in syndrome, with complete loss of horizontal
gaze, pseudobulbar paralysis, and tetraplegia. Although CT
scanning showed a hypodense area within the left side of the
central pons (Fig. 57.39A), cerebral angiography revealed no
 VIRUSES (EXCEPT RETROVIRUSES) AND VIRAL DISEASES 3167

Figure 57.38. Neuroimaging appearance of a patient with delayed cerebral infarction associated with herpes zoster ophthal-
micus (HZO). A, Unenhanced axial CT scan in an 82-year-old woman who developed left-sided HZO. Several weeks later,
she developed a right-sided hemiparesis associated with aphasia and a left gaze preference. The scan shows a low-density
region consistent with an ischemic infarct in the left parietal region (arrow). B, Left internal carotid arteriogram (anteroposterior
view) shows narrowing of the A-1 portion of the left anterior cerebral artery, narrowing of the M-1 portion of the left middle
cerebral artery, and distal segmental beading (arrows). The patient developed progressive encephalopathy and died 120 days
after the onset of the HZO. C, Section through an intracranial vessel shows a necrotizing angiitis, with evidence of infarction
of adjacent white matter. A small region of normal white matter is seen at the lower left (asterisk). Hematoxylin and eosin,
⳯160. (From Hilt DC, Buchholz D, Krumholz A, et al. Herpes zoster ophthalmicus and delayed contralateral hemiparesis
caused by cerebral angiitis: diagnosis and management approaches. Ann Neurol 1983;14⬊543–553.)

abnormalities. Fukumoto et al. (621) described a patient with
cervical (C2) zoster who developed a subarachnoid hemor-
rhage and was found to have granulomatous angiitis of the
basilar artery associated with secondary aneurysm forma-
tion; VZV was identified in the walls of the artery. Powers
(474) reported a case of herpes zoster affecting the maxillary
division of the trigeminal nerve that was complicated by the
delayed occurrence of an occipital infarct (Fig. 57.39D and
E). Finally, Joy et al. (622) described a 24-year-old man who
developed an acute ipsilateral hemiparesis 8 days after he
experienced an attack of herpes zoster oticus. A CT scan
showed changes consistent with a small infarct in the right
 Figure 57.39. Delayed intracranial infarction associated with nonophthalmic herpes zoster. A, In a 54-year-old woman who
developed cervical herpes zoster. Six weeks later, she developed sudden dizziness, an unsteady gait, tinnitus, and double vision.
An examination revealed a left abducens nerve paresis, left facial nerve paresis, and right hemiparesis. She then developed
complete loss of horizontal gaze, tetraplegia, and pseudobulbar paralysis (locked-in syndrome). Unenhanced axial CT scan
shows a hypodense lesion (arrow) on the left side of the pons. The lesion is consistent with a recent ischemic infarction. B,
In a 61-year-old woman who developed right-sided cervical herpes zoster, followed 4 weeks later by acute right-sided retro-
orbital pain and nausea. An examination revealed a right Horner’s syndrome, mild dysarthria, and severe truncal ataxia.
Unenhanced axial CT scan shows a hypodense lesion in the right pons. C, In a 49-year-old woman who developed left-sided
cervical herpes zoster, followed 1 month later by sudden slurred speech, right-sided incoordination, diffuse headache, nausea,
nasal congestion, and chills. Neurologic examination revealed mild dysarthria, left abducens nerve paresis, decreased retroauricu-
lar sensation, marked right-sided dysmetria, and a wide-based gait. Within 48 hours, the patient developed a marked right
hemiparesis and a mild left hemiparesis. Unenhanced T2-weighted axial MR image shows a large region of hyperintensity in
the left pons and a smaller region of hyperintensity in the right pons. D, In a 68-year-old man who developed an acute left
homonymous hemianopic scotoma 3 months after experiencing an attack of right-sided herpes zoster maxillaris, axial CT scan
after intravenous injection of contrast material shows an enhancing lesion consistent with an infarction in the right occipital
lobe. E, Selective right vertebral angiogram (anteroposterior view) in the same patient shows bead-like segmental narrowing
of the proximal right posterior cerebral artery with complete occlusion of the vessel distally. (A, From Willeit J, Schmutzhard
E. Cervical herpes zoster and delayed brainstem infarction. Clin Neurol Neurosurg 1991;93⬊245–247. B, From Snow BJ,
Simcock JP. Brainstem infarction following cervical herpes zoster. Neurology 1988;38⬊1331. C, From Ross MH, Abend WK,
Schwartz RB, et al. A case of C2 herpes zoster with delayed bilateral pontine infarction. Neurology 1991;41⬊1685–1686. D,
and E, From Powers JM. Herpes zoster maxillaris with delayed occipital infarction. J Clin Neuroophthalmol 1986;6:113–115.)

3168
 VIRUSES (EXCEPT RETROVIRUSES) AND VIRAL DISEASES
internal capsule. He was treated with intravenous acyclovir
and made a complete recovery.
Gray et al. (564) described four AIDS patients in whom
herpes zoster-related cerebral vasculitis involved only large
leptomeningeal arteries and was associated with an aseptic
meningitis. Two of the patients had simultaneous thoracic
zoster, one had experienced HZO 2 months earlier, and the
fourth had no history of skin lesions. One case was associ-
ated with a multifocal leukoencephalitis, one with a chronic
ventriculitis, one with an acute meningomyeloradiculitis,
and one with a chronic basal meningitis. Pathologic study
in these four patients revealed multiple cerebral infarcts with
acute and chronic inflammatory changes affecting the vessel
walls of multiple leptomeningeal arteries. Immunostain-
ing for VZV was positive in necrotic foci within the vessel
walls.
The pathogenesis of zoster-related cerebral vasculitis is
unknown, but herpesvirus particles were detected in the
outer layers of the vessel walls of a patient who developed
the condition in the setting of Hodgkin’s disease (610), and
Fukumoto et al. (621) described similar particles in the walls
of a basilar artery with granulomatous angiitis and aneurysm
formation in a patient who died after subarachnoid hemor-
rhage that followed an attack of cervical (C2) zoster. As
noted earlier, Gray et al. (564) identified by immunostaining
VZV in necrotic foci within the walls of leptomeningeal
vessels in four patients with AIDS who developed zoster-
related cerebral vasculitis. These observations suggest that
at least some cases of vasculitis that follow an attack of
herpes zoster result from direct invasion of blood vessels.
The pathway by which the virus reaches the vessels is un-
clear, but it may be contiguous spread from cranial or spinal
nerves, with secondary inflammation and thrombosis (611).
In patients with HZO, the virus may reach the intracranial
vessels through trigeminovascular neurons that are located
in the ophthalmic division of the trigeminal nerve and termi-
nate in the adventitia of ipsilateral intracranial arteries, in-
cluding the internal carotid, anterior cerebral, middle cere-
bral, and superior cerebellar arteries (623).
VZV may be associated with a multifocal leukoencepha-
litis. In 1981, Horten et al. (624) described two patients with
cancer who developed typical herpes zoster in the cervical
and thoracic dermatomes. Several months later, both patients
experienced a progressive multifocal neurologic syndrome
that resembled progressive multifocal leukoencephalopathy
(PML). The clinical features included impaired mental func-
tion, bilateral motor and sensory signs, and focal seizures.
CT scanning revealed asymmetric focal white matter attenu-
ation and peripheral cortical and subcortical hemorrhage,
and examination of the CSF showed a moderate increase in
protein concentration and, in one patient, a mild lymphocytic
pleocytosis. Both patients eventually died, and pathologic
studies showed widespread foci of demyelination, as well
as intranuclear Cowdry type A inclusion bodies in oligoden-
drocytes, astrocytes, and neurons. Analysis of affected cells,
using electron microscopy, showed intranuclear particles
consistent with VZV, and immunocytochemical staining
showed VZV-specific antigens in these cells. Ryder et al.
(625) described an identical syndrome in a patient with
3169
AIDS. Pathologic studies in this patient showed changes
identical to those described by Horten et al. (624), and VZV
antigens were demonstrated in necrotic demyelinated brain
tissue. In addition, VZV-specific DNA was demonstrated
within brain tissue, using Southern blot hybridization. Mor-
gello et al. (626) described two patients with AIDS who
developed pathologically confirmed VZV leukoencephalitis,
even though they had no cutaneous or disseminated VZV
infection within the 6 months preceding the onset of neuro-
logic symptoms and signs. Gray et al. (564) reported four
other cases of VZV multifocal leukoencephalitis in patients
with AIDS.
Amlie-Lefond et al. (627) reported six cases of zoster-
related leukoencephalitis, four in AIDS patients and two in
patients taking immunosuppressive medications. All six pa-
tients developed variable combinations of fever, mental sta-
tus changes, seizures, and multifocal neurologic deficits.
Five of the six had a history of cutaneous zoster. Brain imag-
ing revealed both large and small ischemic and hemorrhagic
infarcts of the cerebral cortex and subcortical white matter
(Fig. 57.40A). Pathologically, the lesions in all six patients
were a combination of ischemia and demyelination (Fig.
57.40B). Infarction in the distribution of large arteries was
accompanied by arteritis of these vessels. Deep-seated in-
farction, often with demyelination, was secondary to small
artery vasculopathy, which was characterized by endothelial
swelling and scant chronic inflammation. The smaller demy-
elinative lesions were usually associated with Cowdry A
inclusion bodies in glia at the periphery of lesions (Fig.
57.40C). This report illustrated that both demyelination and
necrosis can be produced by small vessel vasculopathy and
that zoster-related leukoencephalitis in immunocompro-
mised persons is predominantly a vasculopathy.
The multifocal leukoencephalitis associated with herpes
zoster may be successfully treated if diagnosed at an early
stage. Carmack et al. (628) reported the case of a 13-year-
old boy with acute lymphocytic leukemia in remission on
chemotherapy who was hospitalized because of a 4-day his-
tory of progressive expressive aphasia, perseveration, and
gait unsteadiness in the setting of herpes zoster affecting the
left S2 dermatome. The patient had experienced varicella
about 2 years earlier, and he had experienced two previous
attacks of herpes zoster, one affecting a thoracic dermatome
and the other affecting only the right foot. MR imaging now
showed multiple discrete round and ovoid lesions within
cortical white matter associated with changes consistent with
minimal surrounding cerebral edema. A lumbar puncture
yielded clear fluid with a normal concentration of both pro-
tein and glucose and no significant cellular reaction. A CT-
guided brain biopsy was performed 3 days after admission.
Microscopic sections of the tissue showed well-defined foci
of white matter necrosis, and immunoperoxidase stains, per-
formed on paraffin sections using an anti-VZV monoclonal
antibody, disclosed positive cytoplasmic staining of many
cells within the affected white matter. Electron microscopic
examination of the specimen showed numerous cells con-
taining both complete and incomplete intranuclear viral par-
ticles consistent with the appearance of VZV. A diagnosis
of VZV-associated multifocal leukoencephalitis was made,
 3170 CLINICAL NEURO-OPHTHALMOLOGY
A B
C cephalitis. Ann Neurol 1995;37⬊784–790.)
and the patient was treated with intravenous acyclovir. He
eventually recovered to the point where he had only a very
mild residual aphasia.
Herrold and Hahn (629) described an immunosuppressed
boy who developed a cutaneous eruption of herpes zoster
on his groin and subsequently presented with a subacute
encephalopathy characterized by mental status changes,
aphasia, and hemiparesis. MR imaging of the brain revealed
multifocal bihemispheral target-like lesions predominantly
in the white matter, consistent with a multifocal leu-
koencephalitis. A repeat scan 2 weeks later showed a subcor-
tical hemorrhage in the left insular region. The patient re-
ceived long-term high-dose intravenous acyclovir and
Figure 57.40. Neuroimaging–pathologic cor-
relation in varicella-zoster virus encephalitis. A,
Proton density-weighted axial MR image in a 54-
year-old man taking chronic immunosuppressive
drugs who developed a myelopathy, seizures, and
cerebrospinal fluid pleocytosis. The scan demon-
strates multiple discrete lesions in both hemi-
spheres, primarily involving the white matter and
extending to gray–white junctions. One month
later, the patient developed fever and lethargy,
and a right frontal lobe biopsy was performed.
B, Whole-mount section of the cortical biopsy
shows a well-demarcated ovoid demyelinating
lesion at the cortical gray–white matter junction
(thick arrow). One edge of a larger plaque is seen
at the upper right (thin arrow). Hematoxylin and
eosin, ⳯5. C, Numerous Cowdry type A inclu-
sion bodies (arrows) are present in glia at the
perimeter of the lesions. (From Amlie-Lefond C,
Kleinschmidt-DeMasters BK, Mahalingam R.
The vasculopathy of varicella-zoster virus en-
experienced significant improvement in his neurologic
status.
It seems clear that immunocompromised patients who de-
velop herpes zoster may develop a severe multifocal leu-
koencephalitis caused by VZV similar to that caused by the
JC virus (discussed later); however, herpes zoster-related
leukoencephalitis differs from JC virus-related PML in that
zoster-related leukoencephalitis often has both infarctive (is-
chemic or hemorrhagic) and demyelinative lesions on neu-
roimaging studies, whereas PML has no infarctive compo-
nent and usually produces more coalescent and larger zones
of demyelination on imaging (627). In addition, the bizarre
pleomorphic astrocytes characteristic of PML are not found
 VIRUSES (EXCEPT RETROVIRUSES) AND VIRAL DISEASES
in the brains of patients with VZV leukoencephalitis,
whereas Cowdry A inclusions usually do not occur in the
brains of patients with PML. The detection of VZV DNA
in CSF by PCR and nucleic acid probes confirms the diagno-
sis of zoster-related leukoencephalitis. Early diagnosis of
this condition may permit its successful treatment with mini-
mal neurologic residua.
Postherpetic Neuralgia. As noted earlier, the der-
matome pain that occurs in acute herpes zoster, including
HZO, usually subsides within 2–3 weeks as the rash re-
solves; however, about 10–20% of patients who experience
an attack of typical herpes zoster and 25–50% of patients
over 50 years of age develop postherpetic neuralgia—persis-
tence of pain for more than 4 weeks after the onset of symp-
toms (491,580,634–637). Patients with HZO are even more
likely to experience postherpetic neuralgia (491,635), as are
patients with cancer (247,436).
The pain of postherpetic neuralgia occurs only in the af-
fected dermatome. It tends to be severe, constant, burning,
and lancinating (369). There may be persistent dysesthesia,
hyperalgesia, hypalgesia, or a combination of these. At
times, the sensations are so severe that the lightest touch of
affected skin provokes unbearable pain. Indeed, the pain of
postherpetic neuralgia may be so severe that the patient con-
templates suicide. Postherpetic neuralgia resolves within 1
year in 80% of patients. The remainder of patients with this
condition may suffer with persistent pain for many years.
The pathophysiology of postherpetic neuralgia is unclear.
Both peripheral and central mechanisms are postulated
(630,631). There is preferential loss of larger peripheral
nerve fibers in herpes zoster, and this is thought by some
investigators to impair segmental pain-modulating systems
or to allow increased transmission through unopposed
smaller fibers (635). It is also postulated that dysesthetic
pain in peripheral nerves may be caused by regenerating
pain afferent fibers and that lancinating pain may be caused
by activation of primary pain fibers that invest the affected
nerve trunk (636). On the other hand, some authors believe
that postherpetic neuralgia is caused by central deafferenta-
tion induced by nerve injury (635), and others postulate that
postherpetic neuralgia is related to persistent VZV infection
(637).
Ocular Manifestations. As noted previously, most ocu-
lar manifestations of herpes zoster occur in the setting of
HZO. Some patients, however, develop ocular disturbances
in the absence of typical HZO.
As noted previously, ARN—a diffuse uveitis character-
ized by a peripheral necrotizing retinitis and retinal vasculitis
associated in many cases with anterior chamber inflamma-
tion, vitritis, papillitis, or a combination of these manifesta-
tions (638)—is caused in many cases by VZV (639–646,
646a). Indeed, VZV antigens, VZV DNA, antibodies against
VZV, or a combination of these are detected in ocular tissue
and intraocular fluids in some of these patients, as are viral
particles compatible with VZV (647,648). PCR assay of the
vitreous often documents the presence of VZV DNA (648).
Some cases occur in the setting of HZO, but most develop
in patients after, or concurrent with, extraocular manifesta-
tions of herpes zoster or in immunocompromised patients
3171
with no other evidence of VZV infection. ARN may be a
late event in the course of AIDS (639). In AIDS patients, a
vesicular viral eruption precedes the onset of ARN in
60–90% of cases, a retrobulbar optic neuritis may be present,
and progression to blindness occurs in 76–85% of cases.
The blindness is bilateral in 59% of patients and usually is
caused by retinal detachment. Retrobulbar optic neuritis may
precede ARN in patients with AIDS (539,540). Kang and
Kim (643) described a case of optic neuropathy and central
retinal vascular occlusion as the initial manifestation of
ARN. ARN is not the only form of herpes zoster-associated
retinitis. Another form occurs primarily in patients with
AIDS (644,649–661) and may even be the initial manifesta-
tion of the disease (652). The disorder may be unilateral
or bilateral and superficially resembles ARN, except that it
initially affects only the outer retina and is associated with
little or no intraocular inflammation (Figs. 57.41 and 57.42).
In addition, the peripheral retinal vessels are not significantly
affected in the early stages of the process. The ophthalmo-
scopic appearance is that of a cherry-red spot, combined with
deep white retinal lesions (Fig. 57.43). It rapidly progresses,
resulting in an atrophic, necrotic, and detached retina, a pale
optic disc, and narrowed retinal vessels. The condition,
called progressive outer retinal necrosis (PORN), may recur
despite apparently adequate therapy. PORN may be associ-
ated with zoster-related encephalitis (651,656) (Fig. 57.44).
Shaygani et al. (662) described an HIV-seropositive patient
who developed a bilateral retrobulbar optic neuritis followed
by PORN. In another case, aseptic meningitis and retrobul-
bar optic neuritis preceded VZV PORN in a patient with
AIDS (644). Benz et al. (660) reported two immunocompe-
tent patients treated initially for optic neuropathy with sys-
temic corticosteroids who subsequently developed VZV
PORN. VZV was cultured from samples of CSF taken after
the onset of the visual loss but before the development of
the retinitis, and VZV DNA was detected in the CSF by
PCR.
Most cases of AIDS-associated PORN appear to be caused
by VZV infection. Evidence for this causal relationship is
extensive. First, the onset of the retinitis often follows or is
coincident with an eruption of dermatomal herpes zoster.
Indeed, a history of cutaneous zoster is documented in 67%
of patients (650). Second, VZV can be cultured from
chorioretinal specimens obtained from some patients, and
VZV antigen can be detected in vitreal aspirates from others.
Third, VZV antigen can be detected using immunocyto-
chemistry in the outer retina of eyes with PORN that are
enucleated or have transscleral biopsies. Finally, viral cap-
sids with the size and shape of herpesviruses can be identi-
fied in the outer retina of some enucleated eyes, using elec-
tron microscopy.
The mechanism by which VZV produces PORN in pa-
tients with AIDS remains to be elucidated (651). Pathologic
studies suggest that the retinal infection involves the retinal
pigment epithelium more than the inner retina, consistent
with the clinical impression of an outer retinal necrosis
(652).
A number of intraocular manifestations of VZV infection
have been described in the literature, including anterior uve-
 A B

C D

Figure 57.41. Varicella-zoster virus retinitis in a patient with AIDS. A, Before overt clinical symptoms are present, two small
lesions can be seen superonasal to the fovea. These were initially thought to be cotton-wool spots. B, Three weeks later, there
is marked enlargement of the superior of the two lesions, and there is a new lesion along the inferior temporal branch vein.
C, The appearance of the right ocular fundus at same time as B shows perivascular atrophy with adjacent retinal whitening
from progressive infection. D, Another region of the right ocular fundus exhibits the characteristic multifocal pattern of deep
retinitis in the absence of vitritis. (From Kupperman BD, Quiceno JI, Wiley C, et al. Clinical and histopathologic study of
varicella zoster virus retinitis in patients with the acquired immunodeficiency syndrome. Am J Ophthalmol 1994;118⬊589–600.)

A B

Figure 57.42. Varicella-zoster virus retinitis in a patient with AIDS. A, Fundus photograph at time of referral shows multiple
deep lesions scattered throughout the posterior pole with extensive macular involvement. B, One week later, despite 1 week
of intravenous foscarnet therapy, there has been progression of retinitis with diffuse retinal whitening and development of an
inferotemporal branch vein occlusion characterized by hemorrhage and venous dilation. (From Kupperman BD, Quiceno JI,
Wiley C, et al. Clinical and histopathologic study of varicella zoster virus retinitis in patients with the acquired immunodeficiency
syndrome. Am J Ophthalmol 1994;118⬊589–600.)

3172
 VIRUSES (EXCEPT RETROVIRUSES) AND VIRAL DISEASES 3173

Figure 57.43. Progressive outer retinal necrosis associated with herpes zoster. The patient was a 36-year-old man with AIDS
who developed sudden blurring of vision in the left eye associated with an attack of sacral herpes zoster. A, Initial examination
reveals an area of focal deep retinitis inferior to the left fovea. B, Nine days later, the area of retinitis is larger. C, Three
weeks after the initial examination, there are diffuse multifocal areas of deep retinal inflammation associated with intraretinal
hemorrhages. D, Seven weeks after initial examination, the retina and optic nerve of the left eye are atrophic, and the retinal
vessels are markedly attenuated. (From Margolis TP, Lowder CY, Holland GN, et al. Varicella-zoster virus retinitis in patients
with the acquired immunodeficiency syndrome. Am J Ophthalmol 1991;112⬊119–131.)

itis, iridocyclitis, retinal periphlebitis, and disciform corneal
edema (663–667). In most of these cases, the typical rash
of herpes zoster is absent (zoster sine herpete).
DIAGNOSIS OF VZV INFECTIONS
Both chickenpox and herpes zoster are diagnosed in part
by history and in part by physical examination. For the most
part, the characteristic skin rash, with evidence of lesions
in all stages of development, provides the initial clinical
suspicion. The presence of pruritus, pain, and low-grade
fever, particularly in a child who is not taking antibiotics or
other potentially allergenic drugs, usually is sufficient to
establish a diagnosis of chickenpox. The localization of a
vesicular rash to a particular dermatome suggests herpes
zoster.
The clinical diagnosis of both chickenpox and herpes zos-
ter can be confirmed in several ways (495). A Tzanck smear,
performed by scraping the base of the lesion, may demon-
strate multinucleated giant cells. Standard antibody assays,
such as immune adherence hemagglutination, fluorescence
3174 CLINICAL NEURO-OPHTHALMOLOGY

A B C

Figure 57.44. Encephalitis in a patient with varicella-zoster virus (VZV) retinitis and AIDS. The patient had VZV retinitis
and a congruous right homonymous hemianopia. A, Noncontrast axial CT scan shows an area of hypodensity within the left
posterotemporal-occipital lobe. The atrium of the left lateral ventricle is compressed and displaced slightly anteriorly. B, After
intravenous injection of iodinated contrast material, repeat CT scan at the same level as A shows mild enhancement in the
medial portion of the lesion. C, T2-weighted axial MR image obtained 2 months later shows heterogeneous high signal intensity
in the same location. The involvement of the cortex and the subjacent white matter is consistent with an encephalitis. (From
Kupperman BD, Quiceno JI, Wiley C, et al. Clinical and histopathologic study of varicella zoster virus retinitis in patients
with the acquired immunodeficiency syndrome. Am J Ophthalmol 1994;118⬊589–600.)

antibody to membrane antigen (FAMA), or ELISA, can be
used with both acute and convalescent specimens to demon-
strate either seroconversion or seroboosting. VZV can also
be isolated in susceptible tissue culture lines. The use of
PCR to amplify VZV DNA may be the most sensitive and
specific diagnostic test for both diseases (500,578,579,648,
668).
Diagnosis of neurologic disease related to either HSV or
VZV depends initially on correctly assessing the clinical
setting (241). The association usually is obvious when the
characteristic rash is present or precedes the neurologic signs
and symptoms. Laboratory confirmation of VZV infection
may be achieved by one or more of the following methods:
(a) isolation of the virus from neural tissue, CSF, or both; (b)
demonstration of VZV-specific antigens in affected tissue or
CSF; (c) detection of antibodies against VZV in the serum,
CSF, or both; (d) identification of DNA specific for VZV
in neural tissue, CSF, or both; and (e) electron microscopic
examination of the CSF for VZV particles (500).
TREATMENT OF VZV INFECTIONS
Most patients with chickenpox require increased hygiene,
including bathing, astringent soaks, and closely cropped fin-
gernails to prevent secondary bacterial infection associated
with the pruritic skin lesions. Pruritus can be treated with
topical dressings or the administration of antipruritic drugs.
The fever associated with chickenpox should be treated with
acetaminophen, rather than with aspirin, to prevent Reye
syndrome. Whether or not patients with chickenpox should
be treated with antiviral drugs depends in part on whether
they are adults or children and whether they are immuno-
competent or immunocompromised. Women who are preg-
nant when they develop chickenpox fall into a special cate-
gory.
There is substantial controversy regarding the treatment
of immunocompetent children who develop chickenpox and
who represent 90% of those persons who develop the dis-
ease. Most cases of chickenpox are mild and self-limited,
and children with primary varicella infection who are not
treated with antiviral drugs have the same immune response
to the infection as have patients who are treated (669). Many
authors thus believe that healthy children who develop
chickenpox do not require treatment with either antiviral
drugs or systemic corticosteroids (241). Nevertheless, sev-
eral well-controlled clinical trials showed statistically signif-
icant benefits of antiviral therapy in otherwise healthy chil-
dren with chickenpox (670–676). Such treatment reduces
the duration of clinical illness by several days, particularly
in secondary or tertiary cases within a household, and it
may reduce the frequency of the systemic and neurologic
complications of the disease. It therefore may be appropriate
to consider early antiviral therapy in immunocompetent chil-
dren who develop the disease (673,676).
The same issues regarding treatment of healthy children
who develop chickenpox can be applied to immunocompe-
tent adults (not including pregnant women) who develop
this disease (673). Most probably do not require antiviral
treatment, because the disease is self-limited and without
long-term complications in most patients, and because even
early treatment does not seem to alter either the frequency of
complications or their severity. Nevertheless, complications
from chickenpox in adults can be fatal. It therefore may
be appropriate to treat adults who develop chickenpox with
antiviral treatment (673,676), even though most patients can
be managed with supportive therapy alone.
 VIRUSES (EXCEPT RETROVIRUSES) AND VIRAL DISEASES
In view of the devastating systemic, neurologic, and ocu-
lar effects of congenital and perinatal varicella, the manage-
ment of pregnant women who develop chickenpox or who
are found to be seronegative for antibodies to VZV is of
extreme importance (419). Identified seronegative patients
should be treated promptly with varicella-zoster immune
globulin to minimize the risk of complications in the new-
born (419), and those who show evidence of progressive
infection should be treated with antiviral agents such as
acyclovir (419,673).
As a general rule, immunocompromised patients who de-
velop chickenpox should be treated with antiviral drugs
(241,349,673,674). Acyclovir, vidarabine, and interferon are
the drugs most often used in such patients (500). These drugs
interfere with viral replication, and treatment with one of
them, particularly acyclovir, tends to lessen the severity of
the disease and reduce the incidence of complications, in-
cluding both neurologic and ocular phenomena. However,
other antiviral drugs and novel therapies that are potentially
useful in the treatment of VZV infection are constantly being
developed, and the physician caring for a patient with chick-
enpox may wish to consult an expert in infectious disease
before commencing treatment.
The usefulness of antiviral drugs in altering the natural
history of the cutaneous and neurologic sequelae of chick-
enpox is unclear. There is, however, some evidence that such
therapy may be effective in the treatment of both cutaneous
and neurologic complications of herpes zoster (349,369).
Several placebo-controlled, double-blind trials demon-
strated efficacy of acyclovir for treatment of acute herpes
zoster (673,677–683). The drug accelerates cutaneous heal-
ing, although its effects on the intensity and duration of acute
pain are inconsistent. The prodrugs of acyclovir and pen-
ciclovir, valacyclovir and famciclovir, respectively, are also
used therapeutically. The use of these latter two agents re-
sults in enhanced bioavailability, and both drugs appear to
be superior to acyclovir for acceleration of cutaneous healing
and are at least equally, if not more, efficacious for resolution
of pain (349). Famciclovir has been demonstrated to be as
safe and effective as acyclovir for HZO (684). As noted
earlier, however, new antiviral drugs are constantly being
developed and tested, and acyclovir-resistant strains of VZV
may occur, especially in AIDS patients (680–682). Thus, the
physician caring for a patient with neurologic complications
associated with herpes zoster may wish to consult an expert
in infectious disease before beginning therapy.
Chronic relapsing herpes zoster keratouveitis is a severe
therapeutic problem. Most patients are treated with topical
antiviral agents, topical steroids, or both, but there is consid-
erable controversy as to the relative efficacy of these agents,
alone or in combination.
As noted previously, ARN occurs in some patients with
cutaneous and CNS herpes zoster. The early use of acyclovir,
followed by the addition several days later of oral corticoste-
roids and aspirin, has been associated with significant recov-
ery of visual function in many, although not all, patients
(685–687). Famciclovir and intravitreal antiviral agents
have also been used with success for this condition
(688,689). Some cases of PORN have been successfully
3175
treated with varying combinations of oral, intravenous, and
intravitreal acyclovir, ganciclovir, and foscarnet (507,
659,690–693).
The treatment of postherpetic neuralgia is difficult and
often unsatisfactory (694–696). Although several studies
using early high-dose acyclovir in patients with acute herpes
zoster showed that the drug seemed to reduce the frequency
and severity of postherpetic neuralgia (697–699), most in-
vestigators believe that treatment of acute herpes zoster with
acyclovir or other antiviral drugs does not consistently pre-
vent the development of postherpetic neuralgia, nor does it
reduce the severity of the pain (673,677,700–703). Never-
theless, acyclovir continues to be recommended by some
authors for the treatment of postherpetic neuralgia (699,704),
and in a randomized, double-blind, placebo-controlled, mul-
ticenter trial, oral famciclovir was found to be an effective
and well-tolerated therapy for herpes zoster that significantly
accelerated lesion healing and decreased the duration of
postherpetic neuralgia (705).
Both stellate ganglion block and treatment with systemic
corticosteroids are beneficial in preventing or treating some
cases of postherpetic neuralgia (495). Although they are not
successful in a sufficiently high percentage of patients to
warrant routine use, there is some evidence that early treat-
ment of herpes zoster with systemic corticosteroids may help
to relieve the acute pain of the disease (706), and systemic
corticosteroids are a crucial part of the management of pa-
tients with evidence of zoster-related vasculitis (421).
Analgesics, particularly opioids, are successful in treating
some patients with severe postherpetic neuralgia (632,
707,708). The potential risks of long-term opioid therapy
must be considered, however, when deciding whether to
begin such therapy. Other useful agents include tricyclic an-
tidepressants and anticonvulsant drugs, such as gabapentin,
carbamazepine, and levetiracetam (708–713). Useful topical
agents include capsaicin cream, crushed aspirin dissolved in
chloroform, lidocaine, and ketamine (713–718).
PREVENTION OF VZV INFECTIONS
Prophylaxis of chickenpox in the healthy immunocompe-
tent host is important, even though the disease usually is
benign. Fortunately, transmission of infection can be pre-
vented if necessary by appropriate isolation of the infected
patient. This is a more important concept than it may seem,
because patients with chickenpox who require hospitaliza-
tion are an important source of nosocomial infection within
the hospital environment. Because about 10% of adults are
seronegative for VZV, the risks in the medical care environ-
ment can be extremely high, particularly because those most
likely to become infected are nurses and other medical per-
sonnel caring for the infected patient.
For the immunocompromised host who has not previously
been exposed to chickenpox, both zoster immune globulin
(obtained from patients convalescing from herpes zoster)
and varicella-zoster immune globulin (obtained from pa-
tients convalescing from chickenpox) are useful not only in
preventing symptomatic chickenpox but also in modifying
the course of chickenpox when administered early in the
3176 CLINICAL NEURO-OPHTHALMOLOGY
incubation period (719). Their use provides passive immuni-
zation that may abort clinical disease, prolong the incubation
period, or cause milder disease (495).
As noted earlier, both congenital and perinatal VZV infec-
tions have devastating systemic, neurologic, and ocular con-
sequences. Accordingly, all pregnant women who have
either no history of previous chickenpox or who have an
uncertain history of such an infection should be screened
for antibodies to VZV (720). Women who are found to be
seronegative can then be treated promptly with zoster im-
mune globulin or varicella-zoster immune globulin to mini-
mize the risk of complications in the newborn (720).
A live attenuated VZV vaccine (Oka strain) can be used
to prevent chickenpox in both normal and immunocompro-
mised persons (683,721–723). This vaccine seems to be
safe, immunogenic, and highly protective for a period of
time (495), with over 95% of healthy children developing
both an antibody response and a cell-mediated response
within 6 weeks after vaccination (722). Unfortunately, the
antibody titers gradually wane so that over one third of im-
munosuppressed children are seronegative 3 years after re-
ceiving the vaccine, although 95% of healthy children re-
main seropositive for up to 6 years after immunization (724).
Although uveitis is a potential complication of the varicella
vaccine (725), newer vaccines may give longer-lasting pro-
tection, particularly to immunosuppressed children and
adults, and may cause fewer side effects. There is no proven
treatment to prevent herpes zoster in immunocompromised
patients, although there is evidence that the disease is less
frequent among patients given the Oka strain vaccine than
among patients who previously experienced naturally ac-
quired chickenpox (495). Interestingly, when herpes zoster
occurs in patients who previously have been vaccinated with
the Oka strain vaccine, either vaccine or wild-type strains
of VZV may be recovered. In addition, Masaoka et al. (726)
reported that the use of acyclovir in patients with leukemia
prevented VZV infections during its administration.
Epstein-Barr Virus
EBV virus is a ubiquitous member of the human herpesvi-
rus group of viruses. This virus was first identified in tissue
cultures of biopsy specimens from several patients with Bur-
kitt’s lymphoma in 1964 (727,728). It was subsequently des-
ignated human herpesvirus type 4 and is considered to be a
member of the subfamily of gamma-herpesviruses (241).
Infection with EBV is common, worldwide, and largely
subclinical, with most infections occurring in early child-
hood (728). EBV causes infectious mononucleosis, an im-
portant systemic infection with neurologic and neuro-oph-
thalmologic consequences. In addition, an association exists
between EBV infection and a variety of cancers, including
African Burkitt’s lymphoma, primary cerebral lymphoma
in patients with AIDS, and nasopharyngeal carcinoma
(729–733). An association with multiple sclerosis has been
postulated (733a,733b), but this relationship has not been
confirmed.
Epidemiology
Antibodies to EBV are found in all population groups,
with both sexes equally affected. Antibodies are acquired
earlier in tropical human populations than in industrialized
ones, but even in the United States and Great Britain, EBV
seroconversion occurs before the age of 5 years in about
50% of the population (734). A second wave of seroconver-
sion occurs midway through the second decade of life, and
by adulthood, 90–95% of most populations have demonstra-
ble EBV antibodies (734).
EBV probably is transmitted by intimate contact between
individuals. The virus initially replicates in epithelial cells
in the oropharynx, producing infectious transmissible virus
that is subsequently spread by transfer of saliva during kiss-
ing or other personal contact (735). EBV may also be trans-
mitted by blood transfusion (736) and by liver or bone mar-
row transplant (737,738). The virus in donor bone marrow
can become the dominant virus in the transplant recipient’s
oropharynx, indicating that latently infected hematologic
cells, presumably B lymphocytes, are a common source of
virus for persistent infection of the oropharyngeal epithelium
(737).
Clinical Manifestations
The role of EBV infection during pregnancy and its poten-
tial effects on the fetus are controversial. Several authors
reported that congenital EBV infection could cause multiple
malformations, including heart disease and cataracts (739);
however, most of the cases were not confirmed by specific
immunologic or serologic testing.
Acquired primary EBV infections are commonly asymp-
tomatic in childhood (740). In general, EBV tends to cause
less serious illness when infection occurs in young children
than when it occurs in adults. Acquisition of the virus during
adolescence or early adulthood usually causes symptomatic
disease. The most common primary illness caused by EBV
in humans is infectious mononucleosis. In addition, there is
an association between high titers of EBV antibodies and
various tumors, particularly Burkitt’s lymphoma and naso-
pharyngeal carcinoma.
INFECTIOUS MONONUCLEOSIS
Most patients who become symptomatic from EBV infec-
tion develop infectious mononucleosis, a self-limited febrile
illness that usually resolves spontaneously but that may be
associated with a variety of systemic and neurologic compli-
cations and sequelae (740–743).
Symptoms and Signs. Classic infectious mononucleo-
sis is an acute illness that is characterized clinically by a
sore throat that may be the most severe the patient has ever
experienced, fever, and lymphadenopathy (728,743). The
onset may be abrupt, but some patients experience a short
prodrome of chills, sweats, anorexia, and malaise that may
last several days. Retro-orbital headaches, myalgias, and a
sensation of abdominal fullness are also common prodromal
symptoms.
Fever is present in over 90% of patients with infectious
mononucleosis (728,743). It usually resolves over 10–14
days. A rash that may be macular, petechial, or urticarial, and
that even may mimic the rash of scarlet fever or erythema
multiforme, develops in 5–10% of patients (728,743). The
 VIRUSES (EXCEPT RETROVIRUSES) AND VIRAL DISEASES
pharynx is edematous and is covered with an exudate in
about one third of cases. Palatal petechiae are seen in
25–60% of cases, but they are not diagnostic. They usually
are multiple, 1–2 mm in diameter, and occur in crops that last
3–4 days and then disappear. They most often are located at
the junction of the hard and soft palate. Cervical adenopathy,
usually symmetric, is present in 80–90% of patients. Axil-
lary and inguinal adenopathy are also common. Splenomeg-
aly occurs in about 50% of patients, whereas hepatomegaly
is found in only 10–15% of patients, although even patients
without liver enlargement may have mild tenderness to per-
cussion over the liver. Jaundice occurs in only about 5% of
patients.
Most patients who experience an attack of infectious
mononucleosis recover spontaneously. The sore throat usu-
ally is worst for 3–4 days and then resolves over about 7–10
days. Patients usually remain febrile for about 10–14 days.
The entire illness usually resolves over 2–3 weeks.
Complications of infectious mononucleosis are rare but
significant. For example, rhabdomyolysis was reported in a
single patient by Osamah et al. (744). The most common
complications, however, are hematologic, abdominal, car-
diac, pulmonary, neurologic, and ocular (728,740).
Neurologic complications occur in less than 10% of pa-
tients with infectious mononucleosis (744–746). Neverthe-
less, these syndromes, including encephalitis, aseptic menin-
gitis, multiple cranial neuropathies, optic neuritis, Guillain-
Barré syndrome, transverse myelitis, encephalomyelitis,
psychosis, radiculoplexopathy, and rhabdomyolysis, may
overshadow other manifestations of the illness, and they may
be its first or even only manifestation (728).
EBV-associated encephalitis usually occurs suddenly. It is
typically severe and rapidly progressive (747–754). It most
often takes the form of a brain stem encephalitis or cerebel-
litis, being characterized by truncal ataxia, dysarthria, diplo-
pia, and oscillopsia (755–761).
The neuro-ophthalmologic signs in patients with EBV-
related encephalitis depend on the area of the CNS that is
affected. The opsoclonus-myoclonus syndrome can occur in
children or adults with infectious mononucleosis (762–767).
Delreux et al. (763) described a 71-year-old woman who
developed an acute cerebellar syndrome associated with se-
rologic evidence of EBV infection. The patient complained
of tremulousness, unsteadiness, vertigo, and oscillopsia.
Neurologic examination revealed truncal ataxia, occasional
myoclonic jerks, and opsoclonus. The patient recovered
completely within 8 weeks without treatment. Verma and
Brozman (767) described a 50-year-old man who had fever,
sore throat, and a macular-morbilliform rash 10 days before
hospitalization for the acute onset of oscillopsia, tremulous-
ness, and unsteadiness. Examination revealed opsoclonus,
myoclonus, and marked gait ataxia. He was found to have
an EBV infection and was treated with corticosteroids and
intravenous immunoglobulin. He gradually recovered com-
pletely by 1 year after the onset of symptoms. Cassidy et al.
(768) described reverse and converse ocular bobbing with
synkinetic blinking and opsoclonus in a child with EBV en-
cephalitis after a bone marrow transplant.
Two young patients with infectious mononucleosis de-
3177
scribed by Reis et al. (769) also had abnormal eye move-
ments associated with a cerebellar syndrome. The move-
ments consisted of a conjugate horizontal jerk nystagmus
that changed direction every 3–4 seconds. The authors called
this phenomenon ‘‘short-period alternating nystagmus.’’ All
symptoms and signs resolved completely in both patients
within 5 months.
A patient described by North et al. (756) had, in addition
to ataxia, a left ptosis, diplopia on left lateral gaze, and nys-
tagmus on lateral gaze to both sides. The diplopia may have
been caused by a sixth nerve palsy.
Cotton et al. (757) described a 6-year-old boy who devel-
oped infectious mononucleosis that was complicated by en-
cephalitis characterized by bilateral abducens nerve pareses,
nystagmus, and generalized ataxia. The child initially im-
proved but then deteriorated, developing increasing lethargy,
headache, vomiting, and neck stiffness. Neuroimaging stud-
ies, which previously had been normal except for pansinus-
itis, now showed evidence of hydrocephalus associated with
aqueductal stenosis. The patient was treated with a ventricu-
loperitoneal shunt and eventually recovered normal neuro-
logic function. It was postulated by the authors that direct
infection of the CNS by EBV produced an ependymitis that
led to the aqueductal stenosis.
Ito et al. (770) described a 29-year-old man who devel-
oped acute cerebellar ataxia following EBV infection and
who had antineuronal antibodies in the serum. There was
no identifiable neoplasm, and the ataxia gradually resolved.
These findings suggest that autoimmune mechanisms play
a role in the pathogenesis of some cases of EBV-related
acute cerebellar ataxia.
Not all patients with EBV-associated encephalitis develop
signs and symptoms of brain stem or cerebellar disease.
Some patients develop a more diffuse process that is charac-
terized clinically by headache, lethargy, and confusion
(771,772). Severely affected patients may present in coma
(773). Seizures occur in some cases (774–776), and rare
patients present in status epilepticus (777). Patients in whom
diffuse EBV encephalitis develops are often thought to be
suffering from HSV encephalitis until appropriate hemato-
logic and serologic studies are performed.
Abnormalities in the CSF of patients with EBV-associated
encephalitis usually are mild. The opening pressure is nor-
mal or slightly increased. A mononuclear pleocytosis with
the cell count well below 200 cells/mm3 may be present.
Atypical lymphocytes are often present in the CSF in such
cases. The protein concentration in the CSF is normal or
mildly increased, but the glucose concentration is invariably
normal. Low titers of EBV viral capsid antigen (VCA) may
be present (777), as may EBV genomic sequences and EBV-
specific antibodies (779). These findings suggest that the
neurologic dysfunction is caused by direct invasion of the
CNS by the virus. EBV is almost never cultured from the
CSF during infection, but CSF PCR techniques may be used
to diagnose EBV infection (322). Semiquantitative and
quantitative PCR analysis of EBV DNA suggest that copy
numbers are significantly higher in patients with active EBV
infection compared with levels seen in latently infected pa-
tients who are seropositive for EBV (780,781). Most patients
3178 CLINICAL NEURO-OPHTHALMOLOGY

with EBV-associated encephalitis recover completely
(771,776), although rare patients have persistent neurologic
deficits, seizures, or a combination of these (756). Fatal EBV
brain stem encephalitis may occur (782).
Not all cases of encephalopathy associated with EBV in-
fection are caused by EBV invasion of the CNS. Paskavitz
et al. (783) described a 35-year-old man with an acute mono-
phasic illness characterized by behavior abnormalities, vis-
ual illusions (metamorphopsia), and a seizure, who had evi-
dence by both MR imaging and brain biopsy of multifocal
CNS demyelination (Fig. 57.45). Serologic studies were di-
agnostic of recent EBV infection and included evidence of
intrathecal synthesis of EBV-specific IgG antibodies against
VCA; however, viral DNA could not be amplified from CSF
by PCR, and neither viral antigens nor the EBV genome
could be detected in the brain biopsy specimen. The patient
was thus thought to have a postinfectious EBV-mediated
demyelinating encephalopathy.
The aseptic meningitis that occurs in patients with EBV
infection cannot be distinguished from that caused by a host
of other organisms (784,785). Headache and neck stiffness
are the most common complaints and are almost always as-
sociated with a low-grade fever. The CSF findings in such
patients are identical with those reported in cases of EBV-
associated encephalitis, with a normal opening pressure,
slight mononuclear pleocytosis consisting in part of atypical
lymphocytes, slightly increased protein concentration, and
normal glucose content being the rule. As is also the case
with EBV-associated encephalitis, patients with aseptic
meningitis caused by EBV almost always make a full recov-
ery with no neurologic sequelae.
Cranial nerve pareses occur in some patients with infec-
tious mononucleosis (786). Both unilateral and bilateral pe-
ripheral facial nerve pareses may occur (748,787–788), as
may hypoglossal nerve palsy (789), sudden hearing loss
(790), and a variety of ocular motor nerve pareses. In some
of these patients, there already is evidence of diffuse CNS
disease when the ocular motor nerve pareses develop. In
others, however, the paresis occurs in isolation and may even
be the first manifestation of EBV infection.
Fledelius (791) described a 21-year-old man who devel-
oped diplopia a few days before the onset of fever, headache,
adenopathy, and angina. An examination revealed a partial
left oculomotor nerve paresis. Evaluation of the peripheral
blood revealed changes consistent with infectious mononu-
cleosis, although a heterophile agglutination test was not
performed. The paresis resolved completely about 10 weeks
after the onset of the illness and about 6 weeks after resolu-
tion of systemic symptoms. Nellhaus (792) described a 10-
year-old boy who developed an isolated oculomotor nerve
paresis that developed about 1 month before other manifesta-
tions of infectious mononucleosis. This patient also experi-

A B

Figure 57.45. Demyelinating encephalopathy following Epstein-Barr virus infection. A 35-year-old man presented with an
acute monophasic illness characterized by behavioral abnormalities, visual illusions, and a seizure. MR imaging was performed
1 month after the onset of neurologic symptoms. A, T1-weighted coronal MR image after intravenous injection of gadolinium-
DTPA shows an enhancing lesion in the inferior part of the right temporal lobe. B, Enhanced T1-weighted coronal MR image
more posteriorly shows enhancing lesions in the left parietal lobe and the right posteromedial occipital lobe. (From Paskavitz
JF, Anderson CA, Filley CM, et al. Acute arcuate fiber demyelinating encephalopathy following Epstein-Barr virus infection.
Ann Neurol 1995;38⬊127–131.)
 VIRUSES (EXCEPT RETROVIRUSES) AND VIRAL DISEASES
enced complete resolution of the paresis within 4 months of
the onset of his illness.
An isolated unilateral abducens nerve paresis may be
either the main or the heralding feature of infectious mono-
nucleosis (748,793). Neuberger and Bone (794) described
a 15-year-old girl who developed bilateral abducens nerve
pareses on the 14th day of clinically manifest infectious
mononucleosis. The patient had no other neurologic symp-
toms and signs, although her CSF was never examined.
We saw a 15-year-old boy who developed an acute troch-
lear nerve paresis associated with mild malaise and a low-
grade fever. A complete evaluation was normal except for
serologic evidence of EBV infection, although the patient’s
CSF was normal. He was treated with supportive therapy,
and his diplopia resolved as his systemic condition im-
proved.
Not all patients with ocular motor nerve pareses that occur
in the setting of EBV infection recover completely and rap-
idly. Dolgopol and Husson (795) reported a fatal case of
infectious mononucleosis in which diplopia was one of the
symptoms. Postmortem examination revealed selective de-
generation of cells in the oculomotor and trochlear nuclei.
Davie et al. (796) described a 19-year-old college student
who developed signs and symptoms of a polyradiculoneu-
ritis associated initially with bilateral abducens nerve paresis
and facial diplegia. Within 24 hours, he had complete bilat-
eral external ophthalmoplegia, bilateral ptosis, and pareses
of all remaining motor cranial nerves. He died 6 days later.
No autopsy was performed. Walsh and Hoyt (797) described
a 17-year-old man who developed bilateral ophthalmopar-
esis in the setting of infectious mononucleosis. Like the pa-
tient described by Davie et al. (796), this patient initially
developed bilateral limitation of abduction, followed by total
external ophthalmoplegia. He became unable to breathe
spontaneously and required assisted ventilation. An evalua-
tion of his CSF revealed no abnormality, and he eventually
made a slow but complete recovery.
The site of damage of the ocular motor nerves in patients
with EBV infection is unclear in most cases because most
patients experience complete resolution of their condition.
As noted earlier, the case reported by Dolgopol and Husson
(795) was associated with pathologic evidence of degenera-
tion in the oculomotor and trochlear nerve nuclei. Thus, dam-
age to the ocular motor nerve nuclei is responsible for at
least some cases of ocular motor nerve paresis in the setting
of infectious mononucleosis. On the other hand, such a loca-
tion would not explain the development of unilateral or bilat-
eral abducens nerve pareses, because damage to the abdu-
cens nerve nucleus produces a horizontal gaze paresis, not
an abducens nerve paresis. Thus, the location of damage in
such cases must be in the abducens nerve fascicle or in the
peripheral portion of the nerve in the subarachnoid space,
cavernous sinus, or orbit.
Optic neuritis may occur in patients with infectious mono-
nucleosis (771,798–801). Some of these cases occur in
patients with concomitant or previous EBV-associated
meningitis or meningoencephalitis (771), but most are unas-
sociated with clinical evidence of CNS disease. Most cases
of optic neuritis associated with infectious mononucleosis
3179
are characterized by acute loss of vision in both eyes associ-
ated with bilateral swelling and hyperemia of the optic discs,
but both unilateral and bilateral retrobulbar optic neuritis
can occur (798,800). In some cases of anterior optic neuritis
associated with infectious mononucleosis, there is more ex-
tensive retinal edema than would be expected in a typical
demyelinating anterior optic neuritis, and a star or hemistar
figure composed of lipid develops in the macula. In such
cases, the term ‘‘neuroretinitis’’ is appropriate.
A most unusual case of an optic chiasmal syndrome was
reported by Purvin et al. (802) in a 13-year-old boy with
infectious mononucleosis. The patient developed an illness
characterized by headache, fever, malaise, and abdominal
discomfort. The fever resolved over 2 weeks, but he then
developed posterior orbital pain and blurred vision in the
right eye. An examination performed 6 weeks after the onset
of visual loss revealed visual acuity of 20/40 OD and 20/15
OS. Color vision was slightly reduced in the right eye. Visual
field testing using a Goldmann perimeter revealed a bilateral
superotemporal defect, more extensive in the field of the
right eye. There was a right-sided RAPD, and the right optic
disc appeared pale temporally. Neurologic and systemic ex-
amination results were normal, as were both CT scanning
and MR imaging of the head. A complete blood count re-
vealed a slightly increased white blood cell count of 13,500/
mm3 with 72% lymphocytes, many of which were morpho-
logically atypical. A lumbar puncture showed CSF under
normal pressure. The protein and glucose concentrations in
the CSF were normal, and the fluid was acellular. Laboratory
studies of the patient’s serum and CSF revealed antibodies
to a variety of EBV-specific antigens, and lymphocytic T-
and B-cell subsets as quantitatively defined by the Indiana
University Cerebrospinal Fluid Laboratory were also sup-
portive of an active EBV infection. The patient was not
treated, but within 3 weeks, his visual acuity had improved to
20/15 OU, and his visual field defects had improved. Three
months after the onset of visual symptoms, the patient had
normal visual acuity and visual field in the left eye. The
right eye had visual acuity of 20/15 but showed reduced
contrast sensitivity for all spatial frequencies and a mild tem-
poral hemianopic scotoma by kinetic perimetry. Repeat sero-
logic studies performed at this time demonstrated a marked
reduction in IgM antibodies to VCA (from 1⬊320 during the
acute illness to less than 1⬊10 at this time). Purvin et al.
(802) thought that this patient had a chiasmal ‘‘neuritis’’
caused by EBV infection. Beiren et al. (803) also described
a child with chiasmal neuritis caused by EBV infection.
Papilledema apparently occurs in some patients with in-
fectious mononucleosis (804,805). Many of these patients
do not undergo lumbar puncture, however, and it therefore
is unclear whether the optic disc hyperemia and swelling in
such cases are caused by increased intracranial pressure,
CNS inflammation, inflammation of the optic nerve, or a
combination of these processes.
Guillain-Barré syndrome and its variant, the Miller Fisher
syndrome of ataxia, areflexia, and ophthalmoplegia, occur
in a few patients with infectious mononucleosis or serologic
evidence of EBV infection (806,807). In addition, some
cases of multiple cranial neuropathies associated with poly-
3180 CLINICAL NEURO-OPHTHALMOLOGY
radiculoneuritis in the setting of EBV infection (796,797,
808) probably are variants of EBV-associated Guillain-Barré
syndrome. The clinical manifestations and courses of these
illnesses are indistinguishable from cases unrelated to EBV
infection. Specifically, most patients experience complete
recovery.
Ejima et al. (809) described a 37-year-old woman with
headache, nausea, bulbar palsy, and ataxic speech following
a flu-like illness. She then developed orthostatic syncope,
diffuse body numbness, emaciation, and diminished sweat
production. Neurologic examination revealed anisocoric pu-
pils that were sluggishly reactive to light, impaired left facial
movements, bulbar palsy, convergence nystagmus, areflexia,
an ataxic gait, and severe postural hypotension. CSF showed
albuminocytologic dissociation. Based on clinical, electro-
physiologic, and serum EBV antibody studies, the patient
was thought to have EBV-induced acute pandysautonomia
with diffuse brain stem impairment.
Transverse myelitis can develop in patients with evidence
of EBV infection (56,798,810,811), as can encephalo-
myelitis, myeloradiculitis, and encephalomyeloradiculitis
(812–817). The outcome in these cases is variable, with
some patients having persistent and debilitating neurologic
deficits.
Various psychological and behavior disturbances may
occur during or after infectious mononucleosis. These in-
clude changes in personality, asocial or antisocial behavior,
destructiveness, depression, anxiety, and disturbances in per-
ception (748,818). One of the most interesting perceptual
disturbances that occurs in infectious mononucleosis, often
as the initial manifestation of the disease, is a condition
called the ‘‘Alice in Wonderland’’ syndrome (819–822).
Patients in whom this syndrome develops experience illu-
sions of size, shape, and color of objects. The illusions may
be persistent or intermittent. The duration of visual illusions
ranges from several weeks to several months, during which
time most patients have no other neurologic symptoms or
signs. Neuroimaging is normal in such patients, and EEG is
either normal or shows temporal slow waves. All patients
eventually recover.
Sharma et al. (823) described five patients who developed
a radiculoplexopathy and one patient who developed a femo-
ral neuropathy, all of whom had elevated antibody titers
to various EBV antigens. In all patients, the condition was
characterized by acute or subacute pain and weakness, either
in one leg or asymmetrically in both legs, electromyographic
evidence of denervation in muscles innervated by one or
more major nerves or nerve roots of the lower extremities,
serologic evidence of recent EBV infection, and no evidence
of systemic disease after full radiologic and laboratory inves-
tigations. The prognosis was generally good, with recovery
in weeks to months.
Although neurologic complications are the most frequent
cause of death in patients with infectious mononucleosis,
over 85% of patients with neurologic complications recover
completely (804). The use of systemic corticosteroids in pa-
tients with neurologic disease related to infectious mononu-
cleosis is controversial.
Ocular manifestations of infectious mononucleosis are un-
common but may affect all parts of the eye (824,825). Con-
junctivitis, usually follicular but occasionally membranous,
may occur (806,826); conjunctival nodules consisting of
lymphocytes and plasma cells may appear (827,828); and
episcleritis can develop (829). Pflugfelder et al. (830,831)
described ‘‘dry-eye’’ syndromes in patients during and after
infectious mononucleosis and in patients with serologic evi-
dence of EBV infection but without typical manifestations
of infectious mononucleosis. EBV is also implicated in the
pathogenesis of some cases of Sjögren’s syndrome
(832–834). Both epithelial and stromal keratitis may also
occur in patients with EBV infection (824,825,835–838)
(Fig. 57.46). Periorbital edema and puffiness of the eyelids
may develop in patients with otherwise uncomplicated infec-
tious mononucleosis and may be as severe as that caused by
trichinosis (839). Acute unilateral or bilateral dacryocystitis
may develop during the course of infectious mononucleosis
(840–842), and this condition may even be the presenting
sign of the disease (843). Steele and Meyer (844), for exam-
ple, described an 8-year-old boy who developed redness of
both eyes, sore throat, fever, and fatigue. He then developed
epiphora and swelling of both lower eyelids (Fig. 57.47).
Examination revealed bilateral conjunctivitis as well as dis-
tention of both lacrimal sacs associated with erythema and
tenderness over the distended tissue. Gentle pressure over
the lacrimal sac on the right side resulted in a white mucopu-
rulent discharge from the punctum on that side, whereas
pressure over the lacrimal sac on the left side resulted in a
thick, serous, straw-colored discharge from the ipsilateral
punctum. The findings were thought to be most consistent
with bilateral nasolacrimal duct obstruction and acute dacry-
ocystitis. General physical examination at this time revealed
splenomegaly, generalized lymphadenopathy, pharyngeal
edema and exudate, and a diffuse macular rash over the
face, trunk, arms, and legs. Complete blood count showed
a peripheral lymphocytosis of 56%, with 32% atypical lym-
phocytes, and serologic testing showed a positive heterophile
antibody test. EBV VCA titers were positive for both IgG
and IgM. These clinical and laboratory findings were
thought to be consistent with acute infectious mononucle-
osis.
Intraocular inflammation can occur in association with
infectious mononucleosis. Affected patients may develop
uveitis, bilateral iridocyclitis, white-centered retinal hemor-
rhages, retinal vasculitis, chorioretinitis, or choroiditis
(806,837,845–849). The appearance in some of these cases
is similar to that seen in patients with CMV infection (dis-
cussed earlier). Usui et al. (850) reported detection of EBV
DNA in 75% of CSF specimens from patients with the Vogt-
Kayanagi-Harada uveomeningitis syndrome.
Grossniklaus et al. (851) described the clinical and patho-
logic findings in an 8-year-old boy with bilateral retinal ne-
crosis as a complication of X-linked lymphoproliferative dis-
ease. At age 6, the boy developed decreased vision in his
right eye. Visual acuity was light perception on the right and
20/20 on the left. Fundus examination on the right showed
a shallow exudative and hemorrhagic retinal detachment and
peripheral gray retinal lesions with prominent peripheral
vascular channels and retinal holes. The peripheral retinal
 VIRUSES (EXCEPT RETROVIRUSES) AND VIRAL DISEASES 3181

Figure 57.46. Keratitis associated with infectious mononucleosis. A, Subepithelial infiltrates are present in the cornea of a
patient with infectious mononucleosis. B, Multifocal, granular, discrete, anterior and midstromal opacities are present in the
cornea of another patient with infectious mononucleosis. (From Matoba AY. Ocular disease associated with Epstein-Barr virus
infection. Surv Ophthalmol 1990;35⬊145–150.)

lesions were treated with cryopexy. The disease progressed
over the next 2 years to secondary glaucoma and eventual
total retinal detachment with no light perception in the right
eye. Vision in the left eye declined to 20/50 with eventual
development of a peripheral retinal vasculitis. The patient
was treated with chlorambucil and subsequently died of sep-
sis related to aplastic anemia. Results of the histopathologic
examination of the eyes disclosed retinal necrosis, and exam-
ination using PCR and restriction enzyme analysis showed
EBV DNA in the left eye. Hershberger et al. (852) also de-
scribed a 10-month-old boy with X-linked lymphoprolif-
erative disorder who developed EBV-related bilateral ARN.
Finally, Kramer et al. (853) reported unilateral ARN in a
32-year-old man who was healthy, apart from an EBV infec-
tion with pericarditis that had occurred when he was 17 years
old.
Most of the ocular complications of infectious mononu-
cleosis resolve spontaneously without specific therapy.
Nevertheless, it may be appropriate to treat patients who
have severe intraocular inflammation with topical corticoste-
roids, oral corticosteroids, or both. ARN may require sys-
temic and intravitreal antiviral agents.
Death from infectious mononucleosis is exceptionally rare
but may occur from complications of the disease, such as
thrombocytopenia, granulocytopenia, splenic rupture, he-
patic failure, myocarditis, or encephalitis, or from over-
whelming EBV infection. The latter phenomenon may de-
velop in apparently healthy persons, but it is more frequent
in patients who are rendered immunodeficient from disease
or drugs and in patients with a rare familial immunodefi-
ciency syndrome called Duncan’s syndrome that is transmit-
ted as an X-linked recessive condition (854,855).

EBV INFECTION AND CANCER

Almost all African patients with Burkitt’s lymphoma,

Figure 57.47. Acute dacryocystitis and bilateral nasolacrimal duct ob-
struction in an 8-year-old boy with infectious mononucleosis. Note disten-
tion of right lacrimal sac with overlying erythema and edema (arrowhead).
Similar but less impressive changes are present on the left side. (From
Steele RJ, Meyer DR. Nasolacrimal duct obstruction and acute dacryocys-
titis associated with infectious mononucleosis [Epstein-Barr virus]. Am J
Ophthalmol 1993;115⬊265–266.)
20% of American patients of with Burkitt’s lymphoma, and
most patients with nasopharyngeal carcinoma possess high
antibody titers to EBV (856,857,857a). VCA titers are
10–15 times higher in patients with these tumors than in
matched controls, and DNA hybridization studies demon-
strate the EBV genome in both types of tumor cells (858).
In addition, Epstein-Barr nuclear antigen (EBNA) can be
demonstrated in the nuclei of these cells, and EBV can be
3182 CLINICAL NEURO-OPHTHALMOLOGY
recovered from tissue cultures of biopsy specimens of Bur-
kitt’s lymphoma. Preinvasive lesions of the nasopharynx,
such as dysplasia and carcinoma in situ, are often infected
with EBV, and the EBV DNA found in these lesions is
clonal, suggesting that (a) the lesions represent a focal cellu-
lar growth that arose from a single EBV-infected cell and
(b) EBV infection may be the initiating event in the develop-
ment of nasopharyngeal carcinoma (859). Weisenthal et al.
(860) described a 16-year-old girl who developed a conjunc-
tival mass 6 weeks after an infectious mononucleosis-like
illness associated with a positive Monospot test. Conjuncti-
val biopsy showed a typical Burkitt’s lymphoma, and evi-
dence for EBV infection was found on biopsy of the adenoi-
dal tissue but not in the tumor cells. The lymphoma
responded well to chemotherapy. A direct role for EBV in
the oncogenesis of this sporadic tumor, similar to that noted
in the endemic form of Burkitt’s lymphoma, could not be
supported because EBV-encoded nuclear RNA was absent
in the tumor cells.
Increasing evidence suggests that EBV may be related to
neoplasia in settings other than African Burkitt’s lymphoma
and nasopharyngeal carcinoma (857a). For example, uncon-
trolled EBV-induced lymphoproliferation may occur in pa-
tients with the X-linked recessive immunodeficiency syn-
drome (Duncan’s syndrome, discussed earlier). In addition,
occasional sporadic cases of primary EBV infection evolve
into uncontrolled lymphoproliferative syndromes (861).
EBV may also play a role in the development of Hodgkin’s
disease, particularly that which arises in the neck (862), and
in both B-cell and T-cell systemic and primary CNS non-
Hodgkin’s lymphomas in patients with AIDS, in patients
who have undergone organ transplantation, in patients re-
ceiving immunosuppressive therapy for rheumatologic dis-
eases such as rheumatoid arthritis and dermatomyositis, and
even in immunocompetent persons (863–868). For instance,
Paulus et al. (730) found the EBV genome in primary cere-
bral lymphomas from three patients with AIDS but in none
of 39 sporadic primary cerebral lymphomas, and Bashir et
al. (863,864) found proteins specific to EBV in primary CNS
lymphomas from patients with AIDS. Cinque et al. (729)
detected EBV DNA not only in 16 of 16 primary cerebral
lymphomas that occurred in patients with AIDS but also in
the CSF from all of these patients. In fact, Cinque et al.
(729) found that PCR amplification and restriction enzyme
analysis for EBV DNA in CSF was 100% sensitive and
98.5% specific for AIDS-associated primary CNS lym-
phoma and concluded that this test is a useful diagnostic
tumor marker. EBV-associated leiomyosarcoma of the iris
has been described in a child with HIV infection (869).
Ocular involvement may occur in EBV-associated T-cell
lymphoma. Cochereau et al. (870) described a 51-year-old
man with bilateral serous retinal detachment and choroidal
infiltrates. The diagnosis of lymphoma was made by liver
biopsy. The course of the disease was fulminant and eventu-
ally fatal. Postmortem histologic examination disclosed a
massive infiltration of the choroid and hematopoietic organs
by pleomorphic large T cells. EBV was detected by in situ
hybridization.
The diagnosis of CNS lymphoma is strongly associated
with the presence of EBV DNA in CSF (871). Positive EBV
PCR in the CSF is a sensitive and specific indicator of pri-
mary CNS lymphoma in patients with AIDS and a CNS
mass lesion (322). In the absence of clinical and imaging
features of CNS lymphoma, the presence of detectable CSF
EBV DNA may predict subsequent tumor development in
patients with AIDS (871). Also, EBV DNA monitoring may
be helpful in predicting response to chemotherapy and in
segregating distinct biologic and prognostic categories in
patients with AIDS-related primary CNS lymphoma (872).
Pathology of EBV Infection
A number of histopathologic changes can be seen in the
CNS of patients with fatal infectious mononucleosis (873).
These include degeneration of axons, perivascular cuffing
affecting both arteries and veins, perivascular hemorrhage,
and hyperplasia of astrocytes. Degenerative changes associ-
ated with minimal mononuclear infiltration may occur
throughout the cerebral cortex, basal ganglia, cerebellum,
and spinal cord in such patients. As noted earlier, Dolgopol
and Husson (795) reported a fatal case of infectious mononu-
cleosis in which diplopia was one of the symptoms. Postmor-
tem examination revealed selective degeneration of the ocu-
lomotor and trochlear nuclei. None of the neuropathologic
changes described previously is specific for EBV infection.
Diagnosis of Epstein-Barr Virus Infection
The diagnosis of infectious mononucleosis is made by
evaluation of the blood, which shows several fairly typical
abnormalities (728). First, about 70% of patients have both
a relative and an absolute lymphocytosis. The lymphocytosis
peaks during the second or third week of the illness, at which
time the white blood cell count may be 12,000–18,000/mm3
or higher, with 60–70% of the cells being lymphocytes. Up
to 90% of these lymphocytes may be morphologically
‘‘atypical,’’ and it is this atypical lymphocytosis that is the
hematologic hallmark of infectious mononucleosis, even
though other infectious diseases, including toxoplasmosis,
CMV infection, acute viral hepatitis, rubella, roseola, and
mumps also may be associated with the same phenomenon.
A second hematologic abnormality that often is encountered
in the blood of patients with infectious mononucleosis is a
relative and absolute neutropenia. The neutropenia is mild
in most cases, with total granulocyte counts of 2,000–3,000/
mm3. Nevertheless, some patients with EBV infection de-
velop severe granulocytopenia. A final hematologic distur-
bance that may be present in patients with EBV infection is
thrombocytopenia.
Heterophile antibodies, so named because they not only
cause a visible reaction with the antigen that stimulates their
formation but also cross-react with certain antigens that are
not phylogenetically related to the specific antigen, are pres-
ent in about 90% of patients with infectious mononucleosis
at some point during the illness (728). These antibodies
cause sheep erythrocytes to agglutinate, and the classic het-
erophile antibody titer is reported as the highest serum dilu-
tion at which sheep erythrocytes are agglutinated after ab-
sorption of test serum by guinea pig kidney. Heterophile
 VIRUSES (EXCEPT RETROVIRUSES) AND VIRAL DISEASES
antibodies can also be demonstrated using the Monospot test.
This is a rapid slide agglutination test that is fairly specific
for EBV infection, with less than 3% false-positive results
(874). Heterophile antibodies may be demonstrable at the
onset of the illness, or they may appear later in the illness.
A delayed appearance may be associated with a more pro-
longed convalescence.
Patients in whom EBV infection occurs develop virus-
specific antibodies in addition to the transient heterophile
antibodies. Although serologic studies for virus-specific an-
tibodies, particularly antibodies to VCA, are rarely necessary
because 90% of cases are heterophile-positive, and few
false-positive results are obtained when the test is performed
properly (874), a determination of EBV antibodies may help
to establish a diagnosis in rare cases in which heterophile
antibodies are absent (728), and such antibodies may be pres-
ent in patients with EBV-related CNS manifestations.
EBV may be cultured from oropharyngeal washings or
from circulating lymphocytes in 80–90% of patients with
infectious mononucleosis (875). Facilities for cultivation of
the virus are not, however, routinely available in many diag-
nostic virology laboratories, and this, coupled with the ubiq-
uity of virus shedding in both healthy persons and patients
with unrelated illnesses, renders cultivation of the virus of
little clinical use.
As with almost all infectious diseases, the usefulness of
molecular diagnostic tests based on detection of antigens in
tissue and body fluids (including CSF), using monoclonal
antibodies, and detection of DNA, using PCR with hybridi-
zation, is under investigation in patients with suspected EBV
infection (785,849,876). Although such tests are extremely
sensitive for detection of EBV in the body, they cannot dif-
ferentiate between true infection caused by EBV and infec-
tions caused by other organisms that occur in patients who
also have latent EBV in the body. However, PCR amplifica-
tion of EBV DNA from CNS tissue or CSF appears to be a
reliable test for the diagnosis of EBV-related meningoen-
cephalitis or myelitis because EBV DNA is never present
in the CSF of EBV-seropositive patients with CNS infections
not caused by EBV (754,781,871,872).
Treatment
Treatment of infectious mononucleosis is largely suppor-
tive, because more than 95% of patients recover uneventfully
without specific therapy (728). The level and extent of activ-
ity during convalescence are generally tailored to what the
individual patient can comfortably tolerate; however, contact
sports and heavy lifting should be avoided during the first
2–3 weeks of the illness, especially if splenomegaly is pres-
ent. Analgesics and antipyretics are often helpful.
The use of systemic corticosteroids in the treatment of
uncomplicated infectious mononucleosis probably is unwar-
ranted; however, corticosteroids may be of benefit in patients
with impending airway obstruction, severe thrombocyto-
penia, or hemolytic anemia (728). Systemic corticosteroids
may also be used for patients who develop cardiac or neuro-
logic complications of the disease and for patients with se-
vere intraocular infection.
3183
The efficacy of antiviral agents in patients with EBV in-
fection is unclear. A small double-blind, placebo-controlled
study of patients with infectious mononucleosis who were
treated with intravenous acyclovir showed that the drug in-
terrupted virus shedding in the throat but had minimal effect
on the severity or course of the disease (877,878). On the
other hand, EBV meningoencephalitis has been successfully
treated with ganciclovir (754,879), and it thus is appropriate
to consider antiviral therapy in patients with CNS complica-
tions of EBV infection. As other agents are developed and
tested, the role of antiviral agents in the treatment of EBV
infection may expand considerably.
Cytomegalovirus
Cytomegalovirus (from the Greek words kytos, meaning
‘‘a hollow container,’’ and megalos, meaning ‘‘large’’) is
also called herpesvirus type 5. Like EBV, CMV is found
throughout the world. It shares with other herpesviruses the
unique capacity to remain latent in tissues after recovery of
the host from an acute infection (880). Thus, some persons
infected with CMV develop manifestations from the initial
infection; some develop manifestations from reactivation of
latent virus from a previous asymptomatic infection; and
most remain asymptomatic throughout their lives.
Epidemiology
Studies of the prevalence of antibody against CMV in sera
of the general population show that infection with this virus
is common and usually asymptomatic. CMV infection can
be acquired throughout life; however, most infections are
acquired before age 30. Intrauterine CMV infection occurs
in 1–2% of live births (881), and this rate is sufficient to
make it one of the most common intrauterine infections
throughout the world. The earlier in the course of pregnancy
the infection occurs, the more likely it is that the fetus will
be infected and that clinically apparent disease will result
(882).
From 30 to 60% of persons whose serum is positive for
antibodies to CMV acquire the infection in the perinatal pe-
riod, usually in one of four ways (883). The first source of
perinatal infection is passage through a contaminated uterine
cervix during delivery (parturitional infection). A second
mechanism is transmission from human milk during breast-
feeding or from banked milk. The third mechanism is trans-
mission from other infants in the newborn nursery. Finally,
infants who receive exchange transfusions may develop se-
vere CMV infection.
Young children usually acquire CMV infection from other
children in the family, in day care centers, or in school. This
type of transmission occurs because seropositive children
tend to carry the virus for long periods of time in the respira-
tory and urinary tracts. Such children constantly shed virus in
nasal and oral secretions, as well as in urine, thus providing
several routes for transmission of the virus to seronegative
children with whom they are in contact. There is also some
evidence that such children shed virus in their tears (884),
and it is possible that this is another route for transmission
of the virus. Seronegative children generally do not acquire
3184 CLINICAL NEURO-OPHTHALMOLOGY
infection from adults, because seropositive healthy adults do
not shed virus in either respiratory tract secretions or urine
(880).
Adults and young children can acquire CMV infection
from blood transfusion (885). Infection usually is asymp-
tomatic, but symptomatic infection may occur, particularly
in premature infants, in children and adults who receive mul-
tiple blood transfusions after trauma or invasive surgery, and
in patients with cancer or other debilitative conditions who
receive transfusions of PMNs. CMV infection in adults is
most often transmitted through sexual contact, both hetero-
sexual and homosexual (886). CMV is frequently present
both in the uterine cervix and in semen (880), particularly
in patients who have sexual intercourse at a young age and
who have multiple sexual partners.
Immunosuppressed patients, particularly those who are
chronically immunosuppressed, are at particular risk for both
symptomatic and asymptomatic CMV infection. Such pa-
tients fall into three main groups: (a) patients who have
undergone organ transplantation, (b) patients with malignan-
cies, and (c) patients with AIDS or similar diseases.
Almost all seronegative patients who undergo transplanta-
tion of major organs, such as kidney, liver, heart-lung, and
bone marrow, develop CMV infection (883,887). CMV in-
fections that occur in this setting are new infections. Theo-
retically, the virus may be transmitted from a contaminated
environment, such as a dialysis unit or an intensive care
facility, but the most important sources are infected tissue
and, to a lesser degree, transfused blood (880).
Patients with serologic evidence of previous CMV infec-
tion who undergo organ transplantation may develop symp-
tomatic CMV infection both from reinfection with contami-
nated tissue or blood and from reactivation of latent
infection. The most important factor accounting for reactiva-
tion of CMV infections in this population is the iatrogenic
immunosuppression required for maintenance of the graft.
Cytotoxic drugs, such as cyclophosphamide, azathioprine,
and cyclosporine, alone or in combination, can reactivate a
latent CMV infection and produce significant clinical dis-
ease (888). Interestingly, corticosteroids seem to play only
a minor role in the development of both symptomatic and
asymptomatic CMV infection. Their use alone in moderate
doses does not seem to be associated with an increased risk
of CMV infection after transplantation (880).
The frequency and morbidity of CMV infection in patients
with malignancies are not as high as after major organ trans-
plantation (880). Such patients do not seem to be at a particu-
larly high risk of developing a new CMV infection, even
when they are neutropenic. In addition, even patients with
immunosuppressive malignancies, such as Hodgkin’s dis-
ease, or who are receiving immunosuppressive chemother-
apy usually are not sufficiently immunosuppressed for a long
enough period to develop symptoms and signs from a reacti-
vation infection. Indeed, the major risk of CMV infection
in patients with malignancies is multiple transfusions (dis-
cussed earlier). Despite the relatively small percentage of
patients with malignancies who develop symptomatic CMV
infection, such infection clearly is more common in these
patients than in the normal population (889). When CMV
infection does occur in the setting of an underlying malig-
nancy, it is often associated with severe systemic, neuro-
logic, and ocular manifestations.
There is a close relationship between CMV infection and
AIDS (890–892). Patients with AIDS who are chronically
immunosuppressed have a progressively increased risk of
developing CMV infection the longer they remain alive
(880). Previously seronegative patients may develop new
infection, whereas previously seropositive patients may ex-
perience reactivation of latent infection or new infection
from repeated exposure to a different strain of CMV than
the one that caused the initial seropositivity. Factors associ-
ated with an increased risk of acquiring CMV infection in
patients with AIDS include homosexuality, bisexuality, and
CD4Ⳮ cell counts less than 100/mm3 (893).
Several patients with the disorder known as idiopathic
CD4Ⳮ T lymphocytopenia, a condition similar to that
caused by HIV infection but without evidence of such infec-
tion, can develop CMV infection (894,895). The pathophysi-
ology in such cases is thought to be similar to that in patients
with AIDS.
Clinical Manifestations
Most infections with CMV, as noted previously, are
asymptomatic; however, symptomatic disease may occur in
patients with either primary infection or reactivated latent
infection.
CONGENITAL INFECTION
Many women are infected with CMV, but only a few
transmit infection to the fetus (882). Congenital CMV infec-
tion may be apparent at birth or it may be asymptomatic,
producing manifestations later in infancy or early childhood.
Symptomatic congenital CMV infection is apparent at
birth or shortly thereafter in about 10% of infected infants
(882). Most of these infants have devastating systemic, neu-
rologic, and ocular manifestations similar to those seen in
patients with congenital toxoplasmosis. The classic syn-
drome of congenital cytomegalic inclusion disease (CID) is
characterized by jaundice, hepatosplenomegaly, a petechial
rash, and multiple system and organ damage (883). Affected
infants typically are lethargic, and they often have severe
respiratory difficulties and seizures (880). From 20 to 30%
of these neonates die within several days to weeks, usually
of hepatic dysfunction, bleeding, or secondary bacterial in-
fection. Others survive the first year of life only to become
permanently neurologically handicapped. Such patients may
eventually die of malnutrition, aspiration pneumonia, or
sepsis.
Neurologic manifestations that occur in infants with
symptomatic CMV infection at birth are typically severe and
include microcephaly, porencephaly, hydrocephalus, peri-
ventricular cerebral calcification, mental retardation, deaf-
ness, and seizures (896–898). Malformations of cortical
development (MCD), such as polymicrogyria, cortical dys-
plasia, and lissencephaly, may occur (899). Barkovich and
Lindan (896) proposed that the findings of cerebellar hypo-
plasia and myelination delay in association with diffuse lis-
 VIRUSES (EXCEPT RETROVIRUSES) AND VIRAL DISEASES 3185

Figure 57.48. Chorioretinitis associated with congenital infection with cytomegalovirus. The patient was a 3-month-old girl
who was noted to be photophobic when she was 6 weeks old. A, The right ocular fundus shows a discrete circular area of
scarring and inflammation of the retina, with damage to the retinal pigment epithelium with marginal pigmentation. Dense
white strands extend from the abnormal area into the overlying vitreous. B, The left ocular fundus has a similar appearance.
Viral cultures of the throat and urine from both the patient and her mother yielded cytomegalovirus. (From Lonn LI. Neonatal
cytomegalic inclusion disease chorioretinitis. Arch Ophthalmol 1972;88⬊434–438.)

sencephaly or cortical dysplasia should suggest the diagnosis
of congenital CMV infection. Most of these manifestations
are static, but some infants develop a progressive encepha-
lopathy that eventually ends in death (900). The traditional
gold standard for diagnosis of congenital CMV infection is
detection of the virus in blood, urine, or saliva samples
within the first 3 weeks of life (899). Congenital CMV infec-
tion can also be diagnosed after the first 3 weeks of life by
using PCR analysis of CMV DNA in blood samples (dried
blood spot) (899).
The most common ocular manifestations of CID are
chorioretinitis and optic atrophy, which occur in 5–29% of
cases (901–903) (Figs. 57.48 and 57.49). The chorioretinitis
usually resolves spontaneously over the first several months
of life, leaving residual characteristic pigmented scars simi-
lar to those seen in patients with congenital toxoplasmosis.
Rarely, there is late onset and reactivation of chorioretinitis
in children with congenital CMV infection (904). Other ocu-
lar abnormalities that can occur in patients with CID include
optic nerve hypoplasia (901), optic nerve coloboma and,
megalopapilla (901), uveitis (905), cataract (906), Peters
anomaly (907), microphthalmia (901), and anophthalmia
(908).
Infants with congenital CMV infection who are symptom-
atic at birth but who survive the first few months of life
experience gradual resolution of their systemic manifesta-

Figure 57.49. Optic atrophy associated with con-

genital infection with cytomegalovirus. A, The
right optic disc is normal. B, The left optic disc is
slightly smaller and diffusely pale. Note granular
appearance of peripapillary region caused by re-
duction of visible retinal nerve fiber layer. (From
Hittner HM, Desmond MM, Montgomery JR.
Optic nerve manifestations of human congenital
cytomegalovirus infection. Am J Ophthalmol
1976;81⬊661–665.)
3186 CLINICAL NEURO-OPHTHALMOLOGY

tions, but neurologic and ocular manifestations are perma- tected by serologic testing and treatment with the antiviral
nent, often debilitating (235), and may be progressive (900). agent ganciclovir was associated with control of otherwise
Microcephaly and psychomotor retardation are common in intractable seizures. Harvey et al. (913) described two chil-
such patients, as is sensorineural hearing loss. The hearing dren in whom an acute uveitis occurred during the early
loss tends to be bilateral and may be progressive or stable. progressive phase of Rasmussen’s encephalitis. In both chil-
It usually becomes apparent within the first year of life, but dren, the side of the uveitis was ipsilateral to the side of the
it may not develop or become severe until early childhood. cerebral inflammation, although in one child there also was
Chorioretinal scarring and optic atrophy are also common mild inflammation in the contralateral eye. In one of the
findings in such children. children, the uveitis was associated with an RAPD and swell-
About 90% of neonates with congenital CMV infection ing of the optic disc in that eye (Fig. 57.50). The findings
are asymptomatic at birth (898). Nevertheless, microceph- by Iannetti et al. (912) and by Harvey et al. (913) support
aly, psychomotor retardation, and hearing loss occur in about the theory advanced by Power et al. (911) that Rasmussen’s
6% of these children, and about 2% have chorioretinal scar- encephalitis results from viral infection of the CNS, perhaps
ring, optic atrophy, or both (235). These abnormalities usu- by CMV. Further support for this theory comes from the
ally become apparent within the first 2 years of life work of McLachlan et al. (914), who detected CMV DNA
(903,909). in neurons, glia, and endothelial cells of blood vessels from
cortical material resected from three adults, each of whom
PERINATAL INFECTION had a chronic encephalitis consistent with Rasmussen’s en-
cephalitis.
Children who acquire CMV infection in the perinatal pe-
riod, like children with congenital infection, are often ACQUIRED INFECTION IN IMMUNOCOMPETENT CHILDREN
asymptomatic (898). When clinical manifestations of disease AND ADULTS
are present, they tend to be much less severe than those Otherwise healthy children and adults who develop symp-
caused by congenital infection. In particular, neither diffuse tomatic CMV infection may develop a variety of clinical
visceral damage nor CNS involvement is typically present.
Nevertheless, infants in whom CMV infection results from
exchange transfusions may develop significant clinical dis-
ease (910), as may premature infants who acquire disease
in the neonatal intensive care unit. Symptomatic infants may
develop prolonged respiratory disease or a picture similar to
that of infectious mononucleosis. Subtle manifestations of
CMV infection acquired in the perinatal period include mild
mental retardation and hearing loss that may be mild or se-
vere (903). Such deficits may not become apparent until
early childhood. Retinitis is extremely rare in infants with
perinatally acquired CMV infection, perhaps in part because
of passively acquired maternal immunity, but it may occur
in neonates after transfusion of blood from donors with CMV
antibody titers greater than 1⬊8.
Although most patients with definite perinatal CMV in-
fection do not develop CNS manifestations, Power et al.
(911) performed in situ hybridization with a biotinylated
CMV DNA probe in brain biopsy specimens from 10 pa-
tients with so-called Rasmussen’s encephalitis and 46 age-
matched control patients with other neurologic diseases.
Rasmussen’s encephalitis typically develops in infancy or
early childhood after a prodrome consistent with a viral ill-
ness. It is characterized clinically by intractable partial sei-
zures and focal neurologic deficits and pathologically by
evidence of focal inflammation with microglial nodules in Figure 57.50. Uveitis associated with Rasmussen’s encephalitis. The pa-
neural tissue confined to one hemisphere. Power et al. (911) tient was a 5-year-old girl who developed partial complex seizures with
found CMV genomic material in neurons, astrocytes, oligo- prominent autonomic features. Electroencephalography revealed high-vol-
tage ‘‘k’’ activity and sharp waves in the right temporal region. Ophthalmo-
dendrocytes, and endothelial cells from seven of 10 patients
logic examination 2 months after the onset of seizures revealed normal
(70%) with Rasmussen’s encephalitis but in neural tissue visual acuity, color vision, and visual fields; however, inflammatory cells
from only two of 46 control patients (4.3%). The results of were present in the anterior chamber and vitreous of the right eye, the
this study suggest that at least some cases of Rasmussen’s right pupil was slightly dilated, and there was a right-sided relative afferent
encephalitis are caused by perinatal or early childhood CMV pupillary defect. The right optic disc is swollen and elevated (arrow). (From
infection. Iannetti et al. (912) reported a case of Rasmussen’s Harvey AS, Andermann F, Hopkins IJ, et al. Chronic encephalitis [Rasmus-
encephalitis in which evidence of CMV infection was de- sen’s syndrome] and ipsilateral uveitis. Ann Neurol 1992;32⬊826–829.)
 VIRUSES (EXCEPT RETROVIRUSES) AND VIRAL DISEASES
manifestations. The most common manifestation in such pa-
tients is a mononucleosis that may be indistinguishable from
that caused by EBV (discussed earlier).
CMV-related mononucleosis, like infectious mononucle-
osis caused by EBV infection, is characterized primarily by
fever that is associated with a relative and absolute lympho-
cytosis with abundant atypical lymphocytes (743). The fever
typically lasts 9–35 days, with a mean of 19 days. Other
manifestations of CMV-related mononucleosis are also simi-
lar to those of EBV-related mononucleosis (915), although
patients with CMV-related mononucleosis are somewhat
less likely to have sore throat, an exudative pharyngitis, lym-
phadenopathy, and abdominal pain (743) and more likely to
have a rash, splenomegaly, hepatomegaly, and edema of the
eyelids (743).
Mononucleosis caused by CMV infection is occasionally
associated with a variety of other manifestations, including
interstitial pneumonitis, hepatitis, myocarditis, hematologic
disturbances (e.g., hemolytic anemia, thrombocytopenia),
Guillain-Barré syndrome, and CNS dysfunction. In some
cases, these entities occur simultaneously with the onset of
the constitutional manifestations of the disease or shortly
thereafter. In rare instances, they are the primary or even
the only manifestations of CMV infection.
The Guillain-Barré syndrome is a well-recognized and not
uncommon accompaniment of CMV-induced mononucleo-
sis (916,917). CMV-related Guillain-Barré syndrome can
also occur after kidney or bone marrow transplantation
(918,919). Antibodies to ganglioside GM2 are often associ-
ated with Guillain-Barré syndrome after CMV infection, but
their relevance is not known (916,917). Leonard and Tobin
(920) described the clinical course of CMV-associated Guil-
lain-Barré syndrome and concluded that it was the same as
that of idiopathic Guillain-Barré syndrome. These authors
emphasized that cranial neuropathies were common in these
patients, that sensory function recovered before motor func-
tion, and that complete recovery took about 3 months.
Schmitz and Enders (921) studied 94 patients with Guillain-
Barré syndrome and found serologic evidence of recent
CMV infection in 10 of them (11%). All 10 patients had an
increased protein concentration with a few cells in the CSF,
and all had an atypical lymphocytosis in their peripheral
blood.
Guillain-Barré syndrome is not the only peripheral neuro-
logic disorder associated with CMV infection. CMV infec-
tion may be associated with an IgM anti-MAG/SGPG (my-
elin-associated protein/sulfated glucuronyl paragloboside)
antibody-related chronic polyneuropathy (922).
CMV-associated acute meningoencephalitis occasionally
occurs in immunocompetent children and adults, usually in
the setting of CMV-induced mononucleosis. Some of these
patients have sensory and motor disturbances similar to those
that occur in patients with Guillain-Barré syndrome. They
also report severe headache and photophobia, and they may
have pyramidal tract signs, ataxia, and profound changes in
mental status and alertness (923). In other patients, CMV
encephalitis is characterized by fever, headache, evidence
of meningeal irritation, seizures, and a mild to moderate
alteration in consciousness (924–926). Such patients ini-
3187
tially may be thought to have HSV encephalitis. Phillips et
al. (927) described two such patients, both of whom reported
headache and had mild CSF lymphocytic pleocytosis. In
both patients, CMV was isolated from the urine, from CSF,
and from brain biopsy specimens that also showed prolifera-
tion of microglia and astrocytes associated with focal degen-
eration of neurons. Both patients recovered completely. Two
similar patients were described by Suzuki et al. (928). It
is unclear whether CMV-associated meningoencephalitis is
caused by direct viral invasion of the CNS or by an autoim-
mune response to viral antigens. The presence of CMV DNA
detected by PCR in the CSF suggests direct viral invasion
in some cases and can establish the diagnosis (926).
In addition to the acute form of meningoencephalitis asso-
ciated with CMV infection described earlier, CMV can also
cause a chronic encephalitis in adults. McLachlan et al. (914)
described three adults with chronic encephalitis resembling
Rasmussen’s encephalitis of childhood (discussed earlier).
All three patients had intractable seizures, progressive senso-
rimotor deficits, and cognitive decline that began at 36, 24,
and 16 years of age, respectively. CMV DNA was detected
in resected cortical tissue of all three patients by in situ
hybridization. The DNA was present in neurons, glia, and
endothelial cells of blood vessels. The CMV-positive cells
were not found in any particular distribution in the cortex
or white matter.
The chronic encephalitis caused by CMV that occurs in
immunocompetent adults occasionally has a fatal outcome.
Rousseau et al. (929) reported such a case. A postmortem
examination revealed CMV in the patient’s blood, urine,
skin, muscle, liver, and brain.
Transverse myelitis caused by infection with CMV can
occur in immunocompetent adults (930–932). Presenting
features of the syndrome include a spinal cord sensory level,
weakness with hyporeflexia, flaccid paraparesis or quadri-
paresis, urinary retention, and respiratory failure. In addition,
some patients have bilateral abducens nerve pareses during
the course of the disease (930,931). Recovery is the rule in
patients with this condition.
CMV has been implicated in the etiology of a case of
Vogt-Koyanagi-Harada syndrome (933). The patient was a
previously healthy 30-year-old Portuguese woman who re-
ported progressive visual loss in both eyes. The symptoms
began 24 hours after a flu-like illness. Examination revealed
bilateral findings including impaired visual acuity, cells in
the anterior chamber with non-granulomatous keratic precip-
itates, vitritis, and disc edema. The patient had systemic evi-
dence of acute CMV infection and anti-CMV antibody syn-
thesis in the aqueous humor.
ACQUIRED INFECTION IN IMMUNOSUPPRESSED PERSONS
CMV is the most common virus that secondarily invades
the CNS in patients with AIDS (890,891,934). About 90%
of patients with AIDS have pathologic evidence of CMV
infection (898,935,936). A somewhat smaller percentage of
patients immunocompromised by cancer or after transplanta-
tion also become infected with this virus (898). Although
immunosuppressed and immunodeficient patients who be-
3188 CLINICAL NEURO-OPHTHALMOLOGY
come infected with CMV may remain asymptomatic, most
develop symptomatic disease that is far more extensive and
severe than typically occurs in immunocompetent patients
(discussed previously). Indeed, the longer patients with
AIDS live, the more likely they are to develop symptomatic
evidence of CMV infection. Patients with cancer usually do
not develop symptomatic CMV infection unless they are
aggressively and chronically immunosuppressed; however,
patients with lymphoproliferative disorders, such as Hodg-
kin’s disease, non-Hodgkin’s lymphoma, and leukemia,
seem to be particularly prone to become symptomatic. In
patients who have undergone organ transplantation, the se-
verity of CMV infection is related to two major factors: (a)
the degree and type of immunosuppression and (b) the type
of organ transplanted. With respect to the first factor, Ho
(937) reported that patients treated with antithymocyte glob-
ulin had an increased mortality from CMV infection. With
respect to the second factor, morbidity from CMV is lowest
in patients who have undergone a kidney transplant and high-
est in patients who have received a bone marrow transplant
(880).
The most common manifestations of CMV infection in
immunocompromised patients are fever and mononucleosis
(898). The fever is nonspecific, lasts weeks to months, and
is almost always associated with a moderate atypical lym-
phocytosis that also may last months. After fever and mono-
nucleosis, the most common manifestation of CMV infec-
tion in the immunocompromised patient is pneumonitis
(880). Other manifestations include hepatitis, GI disorders
(e.g., ulcerative colitis, gastric ulcers, pancreatitis, cholecys-
titis), retinitis, and various neurologic disorders.
Although retinitis is an exceptionally rare finding in im-
munocompetent persons with acquired CMV infection
(938), it may cause devastating visual loss in severely immu-
nocompromised patients (939). CMV retinitis occurs in pa-
tients after organ or bone marrow transplantation, in cancer
patients, in patients being treated with immunosuppressive
drugs, in patients with idiopathic CD4Ⳮ T lymphocyto-
penia, and in both adults and children with AIDS (939–943).
CMV retinitis is an important opportunistic infection in pa-
tients with AIDS (943–949).
Highly active antiretroviral therapy (HAART) consists of
combination therapy for HIV infection with at least three
drugs, typically two nucleoside reverse transcriptase inhibi-
tors and either a protease inhibitor or a nonnucleoside reverse
transcriptase inhibitor (949). HAART can result in marked
suppression of HIV replication, improvement of immune
function, increased CD4Ⳮ T cell counts, decreases in oppor-
tunistic infections, and improved survival in patients with
AIDS. In the pre-HAART era, HIV-positive patients with
CD4Ⳮ cell counts below 50 cells/mm3 and those with de-
tectable CMV DNA in their peripheral blood were consid-
ered at high risk for the development of CMV retinitis
(945–947). Indeed, CMV retinitis affected 30–40% of pa-
tients with AIDS at some time during their disease (948,949).
HAART results in restoration of immune function in these
patients. As a consequence, patients with AIDS who are
treated with HAART are less vulnerable to CMV infection
(948). Since the availability of HAART, there has been a
55–95% reduction in the number of new cases of CMV
retinitis (949). Nevertheless, CMV retinitis continues to
occur, albeit at a reduced incidence, and a risk period for
CMV retinitis remains for the first few months after initiat-
ing HAART (950,951). Zambarakji et al. (951) reviewed
longitudinally 1,292 patients for their CD4Ⳮ counts and
HIV load and noted that recurrence and new lesions of CMV
retinitis were more commonly observed in the first 6 months
after starting HAART, but that after 12 months of therapy
recurrences were not observed, even in patients with detecta-
ble HIV loads and low CD4Ⳮ counts. Unfortunately, cases
of HAART resistance or noncompliance are increasingly
being reported, and the emergence of new resistant HIV
strains has occurred in patients failing to respond to HAART
(950), suggesting that the incidence of CMV retinitis in pa-
tients with AIDS may eventually increase.
Patients who develop CMV retinitis typically report
blurred vision in one or both eyes, although when the disease
occurs in the periphery, it may be asymptomatic (945). The
ophthalmoscopic appearance in such cases is typical (952).
The infection usually first appears as cotton-wool spots (soft
exudates) in various areas of the retina, usually in the poste-
rior pole but occasionally in the periphery. Within several
days to weeks, white granular foci of infection develop in
a perivascular distribution that reflects the hematogenous
origin of the virus (953,954) (Fig. 57.51). In many patients,
these perivascular foci develop in the same location as the
previously seen cotton-wool spots. In other cases, however,
they develop in the absence of pre-existing cotton-wool
spots. These early foci of retinitis may be associated with
overlying inflammation in the vitreous, but the reaction usu-
ally is minimal and may even be absent. The lesions gradu-
ally grow and spread by cell-to-cell transmission of infection
over weeks to months, eventually resulting in full-thickness
necrosis of the retina often associated with hemorrhage. Rare
patients develop a peculiar sheathing along the retinal veins
called ‘‘frosted-branch angiitis’’ because of the similarity of
the appearance to frosted tree branches (954,955) (Fig.
57.52). At this stage, the condition may be mistaken for
an ocular inflammatory syndrome of unknown origin that
usually occurs in otherwise healthy persons: acute frosted
retinal periphlebitis (956,957). Some patients with intraocu-
lar CMV infection develop a retinitis most consistent with
ARN (958,959) or PORN (960). Others develop small,
round, depigmented spots that may reflect CMV infection
of the retinal pigment epithelium. Perivascular sheathing,
when present, is associated with a neutrophilic perivascular
infiltrate. Microaneurysms and areas of capillary nonperfu-
sion are also common findings, and macular serous exuda-
tion may occur (961). Patients with severe retinitis may de-
velop an exudative retinal detachment (939,962–967).
Focal, yellow-white, plaque-like lesions and small refractive
bodies caused by intraretinal calcification may appear in
areas of healed retinitis (968).
Since the availability of HAART, patients with AIDS
have enjoyed improvement in their immune status, with re-
duced HIV viral loads and increased CD4Ⳮ counts. Such
patients mount a significant inflammatory response against
CMV retinitis, causing a regression of the CMV infection
 VIRUSES (EXCEPT RETROVIRUSES) AND VIRAL DISEASES 3189

Figure 57.51. Retinitis caused by acquired infection with cytomegalovirus. A, There is an area of retinitis temporal to the
fovea of the left ocular fundus. Note small punctate satellite lesions surrounding the main lesion. Also note a single cotton-
wool spot (soft exudate) superior and nasal to the fovea. B, Progression of retinitis. The area of retinitis is much larger; the
previously seen cotton-wool spot is larger; and several new cotton-wool spots have appeared. (From Flores-Aguilar M, Kupper-
mann BD, Quiceno JI, et al. Pathophysiology and treatment of clinically resistant cytomegalovirus retinitis. Ophthalmology
1993;100⬊1022–1031.)

but a paradoxical visual loss from inflammation (969–975).
These patients develop various signs of posterior segment
inflammation (e.g., symptomatic vitritis, papillitis, cystoid
macular edema, epiretinal membrane formation, prolifera-
tive vitreoretinopathy with spontaneous vitreous hemor-
rhage), anterior segment inflammation (e.g., posterior sub-
capsular cataracts, anterior uveitis, severe post-cataract
extraction inflammation), or a combination of both
(969–975). This syndrome of posterior and/or anterior seg-
ment inflammation associated with immune recovery me-
diated by combination antiretroviral treatment is referred to
as immune recovery uveitis. The highest risk group for this
syndrome consists of patients with extensive CMV disease
(CMV-involved retinal surface area more than 30%)
(322,971). Anterior or posterior immune recovery uveitis
may also occur with improving immune function induced

Figure 57.52. Frosted branch angiitis associated with retinitis caused by infection with CMV. A, Appearance of the right
ocular fundus. Note marked sheathing along the retinal veins in the posterior pole. B, Fluorescein angiogram (late venous
phase) of the right eye shows leakage of dye from the affected vessels. (Figure continues.)
3190 CLINICAL NEURO-OPHTHALMOLOGY

Figure 57.52. Continued. C, Appearance of the right ocular fundus in another patient with frosted branch angiitis associated
with CMV retinitis. The area of angiitis is adjacent to a large area of retinitis. D, Right ocular fundus in a third patient with
CMV retinitis shows extensive frosted branch angiitis throughout the posterior pole. The optic disc is obscured by hemorrhages
and exudates. (A and B, From Geier SA, Nasemann J, Klauss V, et al. Frosted branch angiitis in a patient with the acquired
immunodeficiency syndrome. Am J Ophthalmol 1992;113⬊203–205. C, From Spaide RF, Vitale AT, Toth IR, et al. Frosted
branch angiitis associated with cytomegalovirus retinitis. Am J Ophthalmol 1992;113⬊522–528. D, From Rabb MF, Jampol
LM, Fish RH, et al. Retinal periphlebitis in patients with acquired immunodeficiency syndrome with cytomegalovirus retinitis
mimics acute frosted retinal periphlebitis. Arch Ophthalmol 1992;110⬊1257–1260.)

by intravenous cidofovir given for CMV retinitis (977,978).
Occasionally, immune recovery vitritis is associated with
optic disc neovascularization (979).
The optic nerve may be affected in patients with CMV
retinitis (939,980) (Figs. 57.53 and 57.54). On the basis of
their review of 10 patients with CMV retinitis associated
with optic neuropathy, Gross et al. (981) separated such pa-
tients into two distinct groups. One group of patients with
CMV retinitis and optic neuropathy had a severe isolated
primary CMV papillitis and peripapillary retinitis. These pa-

Figure 57.53. Optic nerve involvement in CMV retinitis. A, Early CMV retinitis in the inferior arcuate region of the left
ocular fundus. The optic disc is normal. B, Extension of retinitis along the inferior arcuate bundle. The inflammatory process
now affects the optic disc. In this case, involvement of the optic disc occurred because of extension of the retinitis. (From
Gross JG, Sadun AA, Wiley CA, et al. Severe visual loss related to isolated peripapillary retinal and optic nerve head cytomegalo-
virus infection. Am J Ophthalmol 1989;108⬊691–698.)
 VIRUSES (EXCEPT RETROVIRUSES) AND VIRAL DISEASES 3191

Figure 57.54. Optic nerve involvement in CMV retinitis. A, The focus of inflammation is centered in and around the right
optic disc. Note extension of retinal edema (arrows). B, In another patient with CMV retinitis, the right optic disc is swollen
and hyperemic, and there is a large focus of inflammation just superior to the disc. In these cases, it is impossible to be certain
whether the inflammation began in and around the disc or spread from the peripapillary region to the disc. (From Gross JG,
Sadun AA, Wiley CA, et al. Severe visual loss related to isolated peripapillary retinal and optic nerve head cytomegalovirus
infection. Am J Ophthalmol 1989;108⬊691–698.)

tients had substantial swelling of the optic disc, obscuration
of vessels on and at the margin of the disc, peripapillary
retinal edema, and lack of retinitis elsewhere. Visual acuity
rapidly deteriorated despite aggressive medical therapy. In
the second group, there was contiguous spread of established
juxtapapillary CMV retinitis to the disc margin, causing a
secondary optic neuropathy associated with the development
of a dense permanent arcuate or altitudinal visual field de-
fect. Central visual acuity was relatively unaffected in these
patients because the macula was not damaged by retinitis.
Although patients with CMV infection may indeed de-
velop a ‘‘primary’’ optic neuritis caused by viral infiltration
of the optic nerve, as suggested by Gross et al. (981), we
believe that most cases of CMV infection in which the optic
nerve is affected are caused by spread of virus from the
juxtapapillary retina into the optic nerve and that the main
distinction is between cases in which there is extensive reti-
nitis and cases in which only the juxtapapillary or peripapil-
lary region is affected. Thus, we prefer to separate patients
with CMV optic neuropathy into three groups: (a) those with
extensive retinitis and spread to the optic nerve; (b) those
with juxtapapillary retinitis with spread to the optic nerve;
and (c) those with primary optic nerve infiltration by CMV.
Regardless of the setting in which CMV-related optic neu-
ropathy occurs, it may be of the anterior or retrobulbar vari-
ety. For example, some patients with extensive CMV retini-
tis affecting the posterior pole develop optic disc swelling
from invasion of the prelaminar portion of the optic nerve
by the virus (982–987). Patients with this form of anterior
optic neuropathy experience acute loss of vision that may
or may not be consistent with the severity of the retinitis.
Other patients with CMV retinitis develop severe anterior
optic neuropathy associated with very little evidence of reti-
nitis. Several patients in the series reported by Gross et al.
(981) would seem to fit into this group, as would several
patients described by Patel et al. (987). In addition, Marmor
et al. (988) described a 51-year-old man with a poorly differ-
entiated large cell (‘‘histiocytic’’) lymphoma who developed
decreased vision in the left eye and was noted to have eleva-
tion of the optic nerve with a focus of presumed retinitis
in the peripapillary region (Fig. 57.55). The condition was
thought to be caused by lymphomatous infiltration of the
optic nerve and retina, and the patient was treated with 3,000
cGy to both orbits. There was no improvement in his ocular
condition. He subsequently died of secondary pneumonia.
At autopsy, both lungs showed evidence of extensive bron-
chopneumonia. A number of epithelial cells contained inclu-
sions consistent with CMV. Microscopic examination of the
left eye revealed that the nasal edge of the optic disc and
adjacent nasal retina were thickened and necrotic. Many of
the enlarged retinal cells contained large eosinophilic nu-
clear inclusions and smaller basophilic cytoplasmic inclu-
sions characteristic of CMV.
Grossniklaus et al. (989) reported a case similar to that
reported by Marmor et al. (988) (Fig. 57.56). The patient
was a 33-year-old man with AIDS who developed decreased
vision in the left eye. Ophthalmoscopic examination re-
vealed focal retinitis associated with vascular tortuosity
along the superotemporal arcade in the right eye. An inferior
peripapillary retinitis associated with a pale swollen optic
disc and adjacent retinal necrosis was present in the left eye.
The patient subsequently died, and the eyes were examined
histopathologically. CMV inclusions were found in all layers
of the affected retinas, including the retinal pigment epithe-
lium. The left optic nerve showed evidence of inflammation
consisting of a mononuclear cell infiltrate that extended just
posterior to the lamina cribrosa. CMV inclusions were found
in distended glial cells in the area of inflammation.
Rare patients with CMV retinitis develop progressive loss
of vision in one or both eyes that is out of proportion to the
3192 CLINICAL NEURO-OPHTHALMOLOGY

Figure 57.55. Primary optic neuritis in a pa-

tient with CMV infection. The patient was a 51-
year-old man who was being treated for a large
cell lymphoma when he developed decreased vi-
sion in the left eye. A, The nasal portion of the
optic disc seems to be swollen. The superior por-
tion of the disc is obscured by a large cotton-
wool spot. The patient was treated with radiation
therapy. He subsequently became progressively
obtunded and died 3 weeks after onset of visual
loss. B, Horizontal section through the superior
portion of the left optic nerve. On the nasal side
(N), there is full-thickness retinal necrosis. On
the temporal side (T), there is a microinfarct of
the retinal nerve fiber layer with cytoid bodies.
Hematoxylin and eosin, ⳯38. C, Higher-power
view of nasal peripapillary retina shows eosino-
philic nuclear inclusions (arrows) surrounded by
clear halos in retinal cells. The inclusions are
morphologically consistent with masses of CMV
particles. Hematoxylin and eosin, ⳯480. (From
Marmor MF, Egbert PR, Egbert BM, et al. Optic
nerve head involvement with cytomegalovirus in
an adult with lymphoma. Arch Ophthalmol 1978;
96⬊1252–1254.)

severity of the retinitis and that is unassociated with optic
disc swelling (981,990). As visual loss progresses in such
patients, the optic disc in the affected eye becomes progres-
sively pale. Patients with this form of retrobulbar optic neu-
ropathy associated with CMV retinitis probably have inva-
sion of the retrolaminar portion of the optic nerve by the
virus.
CMV retinitis and papillitis are important not only be-
cause of their potential effect on vision but also because they
may be the first evidence of disseminated CMV infection
in an immunosuppressed or immunodeficient patient
(881,953). Without systemic therapy, patients with AIDS
who develop CMV retinitis generally do not live longer than
4 months after the onset of visual symptoms (991). With
therapy, not only do they have an improved survival, but
also their vision may increase substantially and remain stable
for the remainder of their lives (987).
CMV-induced meningoencephalitis is not uncommon in
patients who are immunosuppressed or immunodeficient
(992–998). Most of these patients have AIDS, but occasional
cases of encephalitis clearly caused by CMV occur in pa-
tients with cancer and in patients who are immunosuppressed
after organ transplantation (992,999). In addition, patients
with AIDS are at high risk to develop a subacute CMV-
induced encephalitis or ventriculoencephalitis (891,992,
1000–1004) (Fig. 57.57). Many of these patients have evi-
dence of infection by multiple opportunistic organisms, and
it is often difficult to determine the relative roles of the var-
ious organisms in the development of the neurologic mani-
festations. In addition, many cases of encephalopathy once
thought to be caused by CMV are now known to be caused
by the direct effects of HIV on the CNS (i.e., HIV encepha-
lopathy). Thus, the precise role of CMV in the development
of encephalitis in patients with AIDS and the incidence of
true CMV-induced encephalitis in such patients are some-
what unclear. Nevertheless, the results of PCR showing evi-
 VIRUSES (EXCEPT RETROVIRUSES) AND VIRAL DISEASES 3193

Figure 57.56. Primary optic neuritis associated with CMV retinitis. The patient was a 33-year-old man with AIDS who
developed decreased vision in the left eye. Visual acuity was 20/20 OD and 20/60 OS. A, The left ocular fundus shows a
swollen, pale optic disc with adjacent retinal necrosis. The patient died shortly thereafter. B, Longitudinal section through the
left optic nerve shows focal disorganization and necrosis just posterior to the lamina cribrosa (asterisk). Hematoxylin and eosin,
⳯10. C, Higher magnification of the optic nerve shows intranuclear inclusions in distended cells (arrowheads). The inclusions
have a dark-staining center and are surrounded by a halo. Hematoxylin and eosin, ⳯125. D, Immunocytochemical staining
for cytomegalovirus in the optic nerve shows positive staining (arrowheads) in distended cells containing intranuclear inclusions.
PAP, ⳯63. (From Grossniklaus HE, Frank KE, Tomsak RL. Cytomegalovirus retinitis and optic neuritis in acquired immune
deficiency syndrome: report of a case. Ophthalmology 1987;94⬊1601–1604.)

dence of the CMV genome in the CSF of some patients
with subacute encephalopathy and the occurrence of this
encephalopathy in some patients with AIDS who have evi-
dence of systemic and ocular CMV infection support the
contention that it is a true and important entity (994,1000,
1002).
CMV encephalitis in AIDS patients usually presents as a
subacute encephalopathy, often with evidence of prominent
systemic CMV infection (1000). Brain stem encephalitis
with drowsiness, ophthalmoplegia, and gait difficulty may
occur (993,1005). CMV ventriculoencephalitis may present
as a Wernicke’s encephalopathy, with impaired memory,
confabulation, nystagmus, ophthalmoplegia, and ataxia
(1003). CMV encephalitis may develop in patients with
AIDS who are receiving ganciclovir for CMV retinitis
(1006,1007). Indeed, some authors believe that CMV retini-
tis defines a group of patients with AIDS at risk for the
development of CMV encephalitis, particularly when the ret-
initis involves the peripapillary region (1008).
CT scanning in CMV encephalitis often shows periven-
3194 CLINICAL NEURO-OPHTHALMOLOGY

Figure 57.57. Encephalitis caused by CMV. The patient was a 43-year-old man with AIDS who developed a multifocal
encephalitis characterized by saccadic pursuit on tracking to the right, perioral numbness on the left, marked hemisensory loss
on the right side of the body, and minimal left hemiparesis. A, Unenhanced T2-weighted axial MR image shows multiple
lesions in the right basis pontis and the left pontine tegmentum. B, Section through specimen obtained from the pons by CT-
guided stereotactic biopsy shows enlarged cell with intranuclear inclusion. Hematoxylin and eosin, ⳯400. Inset shows electron
micrograph of area. Numerous particles consistent with CMV are present. ⳯14,000. (From Masdeu JC, Small CB, Weiss L,
et al. Multifocal cytomegalovirus encephalitis in AIDS. Ann Neurol 1988;23⬊97–99.)

tricular enhancement, and MR imaging reveals periventricu-
lar lesions with meningeal enhancement or diffuse patchy
lesions throughout the brain (1000,1008,1009). Rarely,
CMV encephalitis presents as a mass lesion (996,
1010,1011). Molecular genetic testing for CMV DNA ap-
pears to be more useful than clinical and neuroimaging find-
ings for documenting CMV infections in patients with AIDS
(994,1000,1012–1016).
An acute disseminated encephalomyelitis may occur after
CMV infection. The clinical manifestations are similar to
those of CMV-related encephalitis. Optic neuritis occurs in
some patients (1017).
CMV infection can cause an aseptic meningitis. The men-
ingitis usually occurs in association with CMV-induced
mononucleosis and develops most often in immunocompro-
mised patients (164). The clinical manifestations of the ill-
ness are those of any aseptic meningitis and include fever,
stiff neck, and lethargy. Cranial neuropathies are rare, and
recovery is the rule unless the infection expands to become
a meningoencephalitis.
CMV infection of the CNS may produce clinical symp-
toms and signs from infarction caused by a vasculitis related
to the infection. Kieburtz et al. (1018) described a 62-year-
old man with AIDS who was being treated for cryptococcal
meningitis when he developed confusion and left-sided
weakness. An examination showed a mild left hemiparesis
associated with neglect of the left side of the body. A CT
scan showed changes consistent with infarction in the right
parietal lobe. The patient continued to receive therapy for
presumed recurrent cryptococcal infection, but his neuro-
logic deficits worsened, and he died 3 weeks later. At au-
topsy, the brain showed widespread necrotic lesions consis-
tent with infarction and associated with local vascular
sclerosis. Cells with cytomegalic cytopathic changes, includ-
ing intranuclear inclusions, and cells that stained positively
with an immunoperoxidase stain directed at CMV-specific
antigens were evident within the walls of affected blood
vessels. Particles consistent with CMV were seen in multiple
organs, including the liver, spleen, adrenal gland, kidney,
and lung, and CMV was cultured from liver and lung speci-
mens.
Two peripheral nerve syndromes caused by CMV occur
in patients with AIDS: (a) subacute ascending polyradiculo-
myelopathy (also called lumbosacral polyradiculopathy or
myelomeningoradiculitis) (1019–1023) and (b) multifocal
neuropathy.
 VIRUSES (EXCEPT RETROVIRUSES) AND VIRAL DISEASES
Subacute ascending polyradiculomyelopathy typically
presents as a subacute ascending hypotonic lower extremity
weakness, often preceded or accompanied by pain and pares-
thesias in the legs and perineum, with areflexia, urinary re-
tention, and loss of sphincter control (1020). Sensory find-
ings vary but include tactile, vibratory, and kinesthetic
impairments, occasionally with a sensory level. Symptoms
typically appear in a patient known to have AIDS, but poly-
radiculomyelopathy also may be the presenting manifesta-
tion of HIV-1 infection (1024). Other causes of lumbosacral
polyradiculopathy in AIDS, such as lymphoma metastases,
must always be considered in the differential diagnosis
(1021), but in patients with polyradiculomyelopathy, the
CSF shows a mixed pleocytosis with prominent representa-
tion of PMNs, an elevated protein concentration, and a low
or normal concentration of glucose. Electrophysiologic stud-
ies reveal features of an axonal neuropathy associated with
varying degrees of demyelination (1019). MR imaging may
show a thickened cauda equina that diffusely enhances after
intravenous injection of paramagnetic contrast material
(1025). Pathologic studies in such cases demonstrate CMV
infiltration of lumbar and sacral nerve roots and the thoracic
and lumbar spinal cords (1019). Some patients respond to
ganciclovir or foscarnet therapy with improvement over
weeks to months (1019,1020,1022), but others fail to re-
spond (1026). Factors predictive of ganciclovir resistance
include persistent polymorphonuclear pleocytosis and hypo-
glycorrhachia on serial CSF studies and a positive CMV
culture from blood or CSF after induction therapy (1020).
CMV multifocal neuropathy is a rapidly progressive sen-
sorimotor neuropathy that occurs in patients with extraneural
CMV infection (including retinitis), cachexia, or fever asso-
ciated with advanced HIV infection and severe immunosup-
pression (1026–1030). The initial symptoms are numbness
and painful paresthesias showing a patchy, multifocal distri-
bution. After several weeks to months, the patient develops
moderate to severe asymmetric sensorimotor neuropathy
(1029). Electrophysiologic studies show an axonal neuropa-
thy (1029), although occasionally a multifocal, predomi-
nantly demyelinating neuropathy is present (1020). CMV
DNA is present in the CSF by PCR in most patients, and
nerve biopsy shows CMV cytopathology and multifocal ne-
crotic endoneurial lesions with infiltrates composed primar-
ily of PMNs (1026). Patients may experience a marked im-
provement with ganciclovir or foscarnet therapy, but
relapses of the neuropathy may occur, and some patients
eventually develop CMV encephalitis (1030).
Pathology
The neuropathology of CMV infection depends to a large
extent on whether the disease is congenital or acquired (297).
In addition, the findings in patients with congenital CMV
infection are related to the stage of gestation at which the
infection occurs (896).
Congenital CMV infection that occurs during the first or
second trimester of gestation is characterized by multifocal
destruction of neural tissue with extensive calcification and
severe inflammation (896). The brain in such cases is small
3195
or represented only by a shrunken, walnut-like mass similar
to that seen in severe congenital toxoplasmosis (581). There
may be abnormalities of cortical architecture and develop-
ment, such as lissencephaly, polymicrogyria in the cerebrum
and cerebellum, porencephaly, mineralization of periventric-
ular structures, and granular ependymitis with hydrocepha-
lus (896). Lissencephaly is thought to occur primarily in
infants who become infected before 16–18 weeks of gesta-
tion, whereas polymicrogyria is thought to develop in infants
infected between 18 and 24 weeks of gestation (896). Other
neuropathologic abnormalities in infants who develop CMV
infection during the first 24 weeks of gestation include aber-
rations of neuronal migration that may result in neuronal
heterotopias, and cystic mineralized areas of tissue destruc-
tion that tend to be less severe than those that occur in con-
genital toxoplasmosis.
The target cells for congenital CMV infection that occurs
during the first or second trimester are the immature cells
in the germinal matrix region. Necrosis of these regions with
subsequent calcification is responsible for the prominent
periventricular localization of the calcification. Microscopi-
cally, there is often an active meningoencephalitis in which
Cowdry type A intranuclear inclusion bodies are found in
many of the neurons, astrocytes, and oligodendrocytes.
These inclusions have an eosinophilic, homogeneous ap-
pearance and often are surrounded by a clear unstained zone,
beyond which lies a rim of marginated chromatin. There
also are focal mineralized lesions in gray and white matter,
where perivascular cuffing, inflammatory glial nodules, and
cells containing inclusions can be seen. Glial scarring may
occur in areas of previous inflammation. The ependymal
surface may be destroyed, or it may show glial proliferation
and scarring or active lesions. The choroid plexus may be
affected. The cerebral aqueduct may become obstructed by
active inflammation or glial scarring. Somewhat less com-
monly, the brain stem and spinal cord show similar lesions
(1031). In chronic cases, microscopic evidence of active in-
flammation may be minimal with only the destructive effects
of the past infection—cystic and mineralized or gliotic
areas—remaining; however, even in such patients, a few
focal areas of perivascular inflammation may still be present,
and cells containing intranuclear inclusions may be identi-
fied (1032).
Congenital CMV infection that occurs during the third
trimester of gestation produces encephaloclastic changes, in-
cluding hydranencephaly, porencephaly, and microcephaly
(1032). Although periventricular infection is present in more
than half the patients, other sites of damage include the cere-
bral cortex, white matter, cerebellum, brain stem, and spinal
cord. Microscopic examination of affected neural tissue in
such patients shows scattered microglial nodules and cyto-
megaly with intranuclear and intracytoplasmic inclusions in
a variety of cell types, including astrocytes, microglia, epen-
dyma, leptomeningeal cells, endothelial cells, and neurons
(1032).
CMV infection acquired during parturition or in the peri-
natal period rarely affects the CNS. When the CNS is af-
fected, there is little evidence of abnormality by gross exami-
nation. Microscopic examination, however, discloses
3196 CLINICAL NEURO-OPHTHALMOLOGY
microglial nodules within which are abnormally large cells
containing intranuclear and intracytoplasmic inclusions.
Pathologic examination in cases of CMV retinitis shows
extensive necrosis and disruption of all layers of the sensory
retina and retinal pigment epithelium. Multinucleated giant
cells may be present, and both retinal cells and retinal pig-
ment epithelial cells may show both intracytoplasmic and
intranuclear inclusions (1033). Electron microscopy of these
inclusions shows that they contain numerous virions that are
morphologically consistent with CMV. In addition, the cells
containing them stain positively when incubated with la-
beled antibodies specific for CMV antigens. Interestingly,
the lesions are restricted by Bruch’s membrane and do not
typically affect the choroid, as occurs in infants and children
with chorioretinitis associated with congenital CMV infec-
tion. Nevertheless, some patients develop a granulomatous
choroiditis subjacent to areas of retinitis. In some cases, the
optic disc is infiltrated by the virus, producing necrosis that
usually does not extend posteriorly much beyond the lamina
cribrosa (953,989). As noted earlier, areas of healed retinitis
may contain intraretinal calcification (968).
Acquired CMV encephalitis in children and adults is char-
acterized pathologically by a diffuse destructive meningoen-
cephalitis with brain swelling and cortical petechial hemor-
rhages (581,997,1009). Microscopic examination in such
cases reveals perivascular cuffing and infiltration, subepen-
dymal inflammation, inflammatory glial nodules, neurono-
phagia, focal necrosis, and many cells containing intra-
nuclear inclusions (581,997,1009,1012,1034). Pathologic
examination in patients with CMV ventriculoencephalitis re-
veals periventriculitis with ependymal necrosis and CMV
intranuclear inclusion bodies (1001). Immunocompromised
patients generally have a more severe tissue response charac-
terized by more extensive necrosis and larger numbers of
cells containing inclusions throughout the cerebral cortex,
cerebellum, brain stem, and spinal cord as well as in the
visceral organs and the eye than do immunocompetent pa-
tients.
Diagnosis
The diagnosis of congenital CMV infection usually is ob-
vious in infants who are symptomatic at birth, particularly
when neuroimaging studies show evidence of cerebellar hy-
poplasia and reduced myelination in association with diffuse
lissencephaly or cortical dysplasia. It can be confirmed by
isolation of the virus in susceptible cell culture systems after
inoculation with urine from the affected infant. A variety of
serologic assays for both IgG and IgM antibodies to CMV
also may be performed but are of little value when adequate
facilities for viral culturing are available. The detection of
CMV DNA by restriction enzyme analysis after amplifica-
tion, using PCR, may be the most rapid and reliable test for
congenital CMV infection (1035,1036).
The diagnosis of acquired CMV infection also may be
suspected on clinical grounds, particularly in immunosup-
pressed patients who develop retinitis, but laboratory tests
should always be performed for confirmation (898). The
diagnosis of CMV infection is made either by direct identifi-
cation of the virus or viral nucleic acid in serum or tissue
or by identification of CMV-specific antigens or antibodies.
Human CMV cannot be readily grown in any experimental
animal, but it can be cultured easily on human fibroblasts.
Cultures usually take 1–4 weeks to become positive, but
the use of cytospin techniques with monoclonal antibodies
directed against CMV antigens shortens the time to less than
48 hours (1037). In addition, CMV nucleic acid can be rap-
idly and accurately detected in body fluids, such as CSF and
vitreous, and in tissues, such as retina and brain, using PCR
and hybridization techniques (1013,1014,1038–1041). For
example, in one study of CMV retinitis in patients with
AIDS, CMV DNA was detected in the vitreous by PCR in
18 of 19 eyes with untreated CMV retinitis and in 19 of 40
vitreous samples from patients with previously treated CMV
retinitis (1042). The presence of CMV DNA in the serum
is a good predictive marker of CMV retinitis in HIV-seropos-
itive subjects (1043). Indeed, identification of CMV nucleic
acid is the quickest and most accurate way to diagnose CMV
infection in both immunocompetent and immunosuppressed
patients (1044). Quantitative PCR of the CSF may even be
useful for monitoring ganciclovir treatment in CMV infec-
tion of the CNS (1002,1045). However, Achim et al. (1046)
found at autopsy an unexpectedly high incidence of positive
CMV PCR results in the CSF of AIDS patients with systemic
CMV infections but without clinical evidence of CMV en-
cephalitis, raising the possibility that a positive CSF PCR
test may not always be a specific indicator of CNS disease
in the presence of coexisting systemic CMV infection.
Indirect detection of CMV, using various antigens to de-
tect antibodies to CMV in the serum, is commonly used to
diagnose CMV infection. A number of different methods to
detect such antibodies may be used, including complement
fixation, immunofluorescent antibody testing, anticomple-
ment immunofluorescence, and ELISA (880,898). The sen-
sitivity and specificity of these tests are generally high and
fairly similar. A diagnosis of infection by any of these tests
requires either a conversion from negative to positive (sero-
conversion) or an elevation of antibody titer over a limited
period of time (880).
Treatment
There is no specific treatment for congenital CMV infec-
tion (1047), although ganciclovir may be beneficial in se-
lected patients (235,1048,1049). Acquired CMV infection,
whether in immunocompetent or immunodeficient patients,
is treated with one or more antiviral drugs. Options for sys-
temic therapy for CMV disease include ganciclovir, foscar-
net, a combination of ganciclovir and foscarnet, cidofovir,
fomivirsen, and valganciclovir (322,898,995). Antiviral
drugs may have diminished effectiveness in immunosup-
pressed patients or they may suppress the virus for only as
long as they are administered because of the absence of criti-
cal host defenses essential for their optimal effect. Thus, the
infection reappears when the drugs are stopped. In addition,
treatment may lead to other complications. Before the
HAART era, an open-label trial of combination therapy
(ganciclovir and foscarnet) for CMV encephalitis and myeli-
 VIRUSES (EXCEPT RETROVIRUSES) AND VIRAL DISEASES
tis demonstrated clinical improvement or stabilization dur-
ing the induction phase in 74% of patients (1050); even so,
overall survival was only 94 days. Antiretroviral (HAART)
therapy may improve the prognosis (322).
Treatment for CMV retinitis includes intravitreal gan-
ciclovir given by injection or implants, intravitreal foscarnet,
or intravitreal fomivirsen. These drugs frequently are used
in combination with intravenous ganciclovir, intravenous
foscarnet, intravenous cidofovir, or oral valganciclovir
(1051–1058). Cidofovir (HPMPC), an acyclic nucleoside
analog, may induce prolonged arrest of progression of CMV
retinitis when given intravenously or by intravitreal injec-
tion, but it also may cause serious ocular complications, es-
pecially iritis and chronic hypotony (1059–1061). Even with
such treatment, there may be progression of the retinitis be-
cause of acquired drug resistance. In addition, up to 30% of
patients develop a rhegmatogenous retinal detachment after
treatment with antiviral drugs, particularly ganciclovir
(1062), and direct retinal toxicity may occur with high-dose
ganciclovir injections (1063). As noted earlier, since the use
of HAART, there has been a significant reduction in the
number of cases of CMV retinitis in AIDS patients, and
there is an increasing prevalence of patients with AIDS and
CMV retinitis who experience immune reconstitution as a
consequence of HAART. In addition, since HAART, it has
been demonstrated that anti-CMV therapy may be discontin-
ued for prolonged periods of time in some patients whose
CMV retinitis remains healed with therapy for greater than
4 months and who demonstrate sustained HAART-induced
elevation of CD4Ⳮ cell counts (949,1064,1065). It is impor-
tant to monitor these patients closely by ophthalmoscopic
examination and CD4Ⳮ levels, however, because HAART
failure may occur and allow CMV retinitis reactivation
(949,1064,1065).
Prophylaxis
The only available CMV vaccine may have at best a mar-
ginal effect in preventing symptomatic CMV disease caused
by primary infection. Other types of vaccines, such as sub-
unit and recombinant vaccines, are being developed.
In immunosuppressed patients who are seropositive for
CMV, the use of prophylactic antiviral drugs, such as
acyclovir or ganciclovir, may prevent reactivation of latent
virus (898,1066). Seropositive patients treated in this fashion
are said to have a reduced risk of developing CMV pneumo-
nia. It is unclear whether such patients are also less likely
to develop other complications of CMV reactivation, such
as retinitis and encephalitis. In a double-blind, placebo-con-
trolled trial of low-dose ganciclovir to prevent CMV disease
after heart transplantation, prophylaxis did not reduce the
incidence of clinical CMV disease in CMV-positive patients
but did delay its onset and reduce its morbidity (1067). In
addition, it significantly reduced the incidence of CMV dis-
ease in CMV-negative heart transplant recipients who had
received organs from CMV-positive donors. Ganciclovir or
acyclovir prophylaxis, occasionally combined with intrave-
nous immune globulin, significantly reduces the incidence
of CMV disease in both CMV-positive and CMV-negative
3197
liver transplant and bone marrow transplant recipients
(1068–1072).
Human Herpesvirus Type 6
Human herpesvirus 6 (HHV-6), initially called ‘‘B-
lymphotropic virus’’ because it was first isolated from lym-
phocytes obtained from HIV-infected patients (1074), has a
structure similar to that of the other herpesviruses (1075).
Two distinct variants of HHV-6 exist, called variant A and
variant B (1075). There is some evidence that variant B is
the cause of most symptomatic HHV-6 infections (1076).
It seems clear that HHV-6 is transmitted primarily from
mother to child, because molecular genetic techniques show
that viral isolates differ among families with evidence of
HHV-6 infection but are identical within families (1077).
The method by which the virus is transmitted between
mother and child, however, is unknown. It is also possible
that infectious virus is transmissible through sexual contact
(1078) and blood transfusion (1079).
Most persons with evidence of HHV-6 infection are
asymptomatic. Nevertheless, there is increasing evidence
that primary HHV-6 infection causes a wide variety of disor-
ders in both children and adults and that reactivation of latent
virus in a previously infected but asymptomatic person may
occur under certain circumstances, particularly transient or
permanent immunosuppression, resulting in disease that is
severe, long-lasting, or both (1080). HHV-6 infection occurs
frequently in organ transplant recipients but is not usually
associated with severe clinical manifestations (1081).
Primary HHV-6 infection is thought to be the cause of a
mononucleosis-like syndrome associated with a rash resem-
bling roseola that occurs primarily in infants and children
and is called exanthem subitum, roseola infantum, or sixth
disease (1075,1077). The last designation is derived from
the common assignation of Roman numerals I–VI to exan-
thems of childhood in the late 19th century. It is generally
believed that HHV-6 persists in the host after recovery from
exanthem subitum and that active virus is intermittently or
continuously shed from the oropharynx in such patients
(1082).
Both primary HHV-6 infection and reactivation of latent
virus may be responsible for many of the nonspecific febrile
syndromes, particularly those associated with otitis media,
that occasionally occur in infants and young children (1083).
An illness resembling infectious mononucleosis, hematolog-
ically characterized by atypical lymphocytosis in the periph-
eral blood and liver dysfunction, may occur in children with
HHV-6 infection (1084). In addition, evidence of HHV-6
infection may be found in some children who experience
single or recurrent febrile seizures or febrile status epilep-
ticus (1085–1091). It is thus possible that HHV-6 invades
the brain during the acute phase of exanthem subitum and
that reactivation of the virus at a later date induces febrile
seizures in such patients.
Primary infection with HHV-6 may produce a febrile syn-
drome not only in children but also in adults. Akashi et al.
(1092) described a 43-year-old man who developed a severe
infectious mononucleosis-like syndrome that probably was
3198 CLINICAL NEURO-OPHTHALMOLOGY
caused by a primary infection with HHV-6 type B. Also,
HHV-6 may cause severe pneumonitis or fulminant hepatitis
in immunocompetent adults (1093).
Primary infection with HHV-6 apparently may cause fatal
infections in previously healthy patients. Prezioso et al.
(1094) described an 11-month-old immunocompetent girl
who developed fever, a rash, and multisystem disease. She
eventually died of cardiac failure. Postmortem examination
revealed evidence of widespread infection with HHV-6, sug-
gesting that infection with this virus can cause disseminated
disease.
Primary HHV-6 infection may occur in patients who are
debilitated or immunosuppressed. Corbellino et al. (1095)
used PCR to detect HHV-6 genetic sequences in tissues ob-
tained at necropsy from five patients who died of AIDS
and from two persons who died of accidental causes. In the
patients with AIDS, HHV-6 DNA was detected in the vast
majority of tissues analyzed, including cerebral cortex, brain
stem, cerebellum, spinal cord, and paravertebral ganglia,
whereas viral nucleic acid was identified in a much lower
percentage of tissues in the two persons who were seronega-
tive for HIV. Similar results were reported by Knox and
Carrigan (1079). These results suggest that persons who are
terminally ill with AIDS may also have widely disseminated
infection with HHV-6, although it remains unclear whether,
and to what degree, the infection contributes to the death of
such patients.
HHV-6 DNA is sometimes detected in T- and B-cell sys-
temic lymphomas (1096), in Hodgkin’s disease (1097), in
primary cerebral lymphomas that occur in patients with
AIDS (730), in other AIDS-related non-Hodgkin’s lym-
phomas (1098), in hemophagocytic syndrome (1099), in leu-
kemic cells (1100), and in other myelodysplastic and myelo-
proliferative disorders (1101). HHV-6 can also be isolated
from some cervical cancer cells (1102). HHV-6 variant A
was detected in CSF, serum, and tumor tissue in a child
with diffuse leptomeningeal oligodendrogliomatosis (1103).
These findings suggest that the virus may be oncogenic in
certain settings. HHV-6 may also be etiologically linked to
sinus histiocytosis with massive lymphadenopathy (Rosai-
Dorfman disease), a rare, usually benign disease of children
and young adults primarily manifested by painless cervical
lymphadenopathy (1104).
Because antibody levels are low in adults, and because
it is difficult to isolate HHV-6 from the blood of healthy
immunocompetent persons, except during primary infection,
it seems that recurrent HHV-6 infection with viremia and
increasing antibody titers is rare in the normal population.
On the other hand, there is increasing evidence that HHV-
6 may become activated in patients who become transiently
or permanently immunosuppressed, thus resulting in symp-
tomatic infection (1105). For instance, HHV-6 can be de-
tected in the lymphocytes of patients experiencing rejection
after solid organ transplantation (1079), suggesting that reac-
tivation of the virus may play a role in the rejection phenom-
enon.
Some authors believe that recurrent HHV-6 infection can
occur in patients with primary CMV infection (1081,1106).
For example, HHV-6 DNA was detected in retinal tissue
from two patients with AIDS and retinitis of unknown origin
(1107), transcriptional activity of both HIV-1 and HHV-6
was detected in retinal tissue from 7 of 26 patients with
AIDS (1108), and antigens specific for HHV-6 were de-
tected immunohistologically using monoclonal antibodies in
the retinas of several patients with CMV retinitis in the set-
ting of AIDS (1109,1110). The role of HHV-6 in the produc-
tion of ocular disease in patients with AIDS is unclear, but
it may act synergistically with other herpesviruses (1110,
1111,1995).
HHV-6 may be associated with the development of CNS
disease in both immunocompetent and immunosuppressed
persons (1089–1091,1112). Review of CSF specimens from
immunocompetent patients initially suspected of having
HSV encephalitis found HHV-6 DNA in about 7% of speci-
mens (1113), and HHV-6 DNA also was found in specimens
from the mesial temporal lobe in four of eight patients who
underwent surgery for mesial temporal lobe epilepsy (1114).
These results suggest that HHV-6 may be a more important
cause of sporadic encephalitis then previously appreciated.
HHV-6 encephalitis has been described after transplantation
procedures (1115–1117) but may also occur in immunocom-
petent individuals (1118). It also has been described as a
component of hypersensitivity syndrome (1119).
Huang et al. (1120) described two young children, a 7-
month-old girl and a 4-month-old boy, in whom this virus
appeared to have caused an aseptic meningitis associated
with otherwise typical exanthem subitum, and several au-
thors have described cases of meningoencephalitis associ-
ated with exanthem subitum and evidence of HHV-6 in
blood, CSF, brain tissue, or a combination of these
(1121–1128). In some of these cases, the primary process
is a leukoencephalitis resembling PML. In others, both white
matter and gray matter are affected.
Mackenzie et al. (1129) described a previously healthy
elderly woman with a chronic myelopathy associated with
HHV-6 infection. She committed suicide after 2 years of
progressive spastic paraparesis, and at autopsy the spinal
cord showed widespread demyelination, axonal loss, and
chronic inflammation. HHV-6 DNA was detected in spinal
cord tissue using PCR and restriction enzyme analysis, and
glial cells were immunoreactive with an HHV-6 antibody.
Buchwald et al. (1130) evaluated a cohort of 259 patients
with a chronic fatigue syndrome characterized by malaise,
neurologic disturbances, and immunologic abnormalities for
evidence of HHV-6 infection using a variety of techniques,
including primary cell culture of lymphocytes, assays using
monoclonal antibodies specific for HHV-6 proteins, and
PCR with nucleic acid probes specific for HHV-6 DNA.
These investigators found that 70% of the patients had evi-
dence of HHV-6 infection, compared with 20% of an age-
matched control group. The neurologic disturbances in the
patient group included a primary seizure disorder (7 pa-
tients), acute transient ataxia (10 patients), and transient pa-
resis (8 patients). None of the patients had any permanent
deficits, but MR imaging showed foci of high signal intensity
on T2-weighted images, typically punctate but occasionally
larger patchy areas, in 113 of 144 patients (78%) compared
with 10 of 47 (21%) age-matched, healthy controls. HHV-
 VIRUSES (EXCEPT RETROVIRUSES) AND VIRAL DISEASES
6 may also contribute to the pathogenesis of AIDS encepha-
lopathy (1131).
Merelli et al. (1132) used indirect immunofluorescence
analysis to evaluate titers of antibodies to HHV-6 in the
blood and CSF of 28 patients with ‘‘idiopathic’’ Guillain-
Barré syndrome, 63 patients with other neurologic diseases
(e.g., migraine, dizziness, seizures), and 150 healthy control
subjects. These authors found higher titers of antibodies to
HHV-6 in the patients with Guillain-Barré syndrome com-
pared with patients in the other two groups. The findings of
Merelli et al. (1132) could not be confirmed by Wilborn et
al. (1133), however, who found no evidence of HHV-6 DNA
and no increase in antibodies against HHV-6 in paired sam-
ples of serum and CSF from seven patients with Guillain-
Barré syndrome. Miyake et al. (1133) reported a female in-
fant who developed Guillain-Barré syndrome 20 days after
having exanthem subitum confirmed serologically as HHV-
6 infection.
The association of active HHV-6 infection and multiple
sclerosis is controversial. Some investigators have found
viral DNA and antigens in oligodendrocytes and other cells
surrounding multiple sclerosis plaques, immunohistochemi-
cal evidence of HHV-6 in the plaques themselves, and HHV-
6 DNA or anti-HHV-6 IgM antibodies in blood and/or CSF
of patients with multiple sclerosis (1134–1142). Other
studies, however, have found no evidence to support a role
for HHV-6 in the pathogenesis of multiple sclerosis
(1143–1146).
As with the other herpesviruses, HHV-6 can be detected
by serologic tests designed to detect antibody to the virus
(1135,1147). Qualitative and quantitative PCR techniques
can be used with restriction enzyme analysis to identify
HHV-6 DNA in serum, plasma, or CSF (1074,1148).
No clinical trials of antiviral drug therapy for HHV-6 in-
fection have been performed to date (322). The sensitivity
of HHV-6 to antiviral agents appears to be similar to that
of CMV, with most isolates being resistant to acyclovir but
sensitive to ganciclovir, valganciclovir, foscarnet, and cido-
fovir (1149).
Human Herpesvirus 7 and Human Herpesvirus 8
Human herpesvirus type 7 (HHV-7) is a T-lymphotropic
virus that is capable of infecting both CD4Ⳮ and CD8Ⳮ
lymphocytes and that is genetically similar to both CMV and
HHV-6 (1074). This virus, like other herpesviruses, seems to
be widely infective, with a prevalence rate in the United
States of over 85% (1150). Wyatt et al. (1151) concluded
that infection with HHV-7 occurs during childhood but at a
somewhat later age than the very early age documented for
HHV-6; however, Clark et al. (1152) tested a much larger
group of children and found that antibodies to HHV-7 were
present in more than 94% of children under 2 months of
age. Both groups of investigators found antibodies to the
virus in over 96% of adults. The virus seems to be a common
inhabitant of saliva and can be isolated from this fluid in
both adults and children (1153). The significance of infec-
tion with HHV-7, however, is largely unknown, although it
may cause some attacks of exanthema subitum (1154,1155)
3199
and hepatitis (1156). HHV-7 may cause encephalitis, but
only a few cases have been reported (1157,1158).
Human herpesvirus 8, a herpesvirus discovered by Chang
et al. in 1994 (1159), is thought to be responsible for induc-
ing AIDS-associated Kaposi’s sarcoma, classic Kaposi’s sar-
coma, and the Kaposi’s sarcoma that occurs in HIV-negative
homosexual men (1160,1161). It thus is also called Kaposi
sarcoma-associated herpesvirus (KSHV). Indeed, Whitby et
al. (1162) reported that HIV-infected patients who have
HHV-8 DNA in their peripheral blood mononuclear cells
have an increased risk of developing Kaposi’s sarcoma.
HHV-8 also has a pathogenic role in AIDS-related body
cavity-based lymphomas (primary effusional lymphoma),
multifocal Castleman’s disease, multiple myeloma, and
a variety of benign lymphoid proliferations including
angioimmunoblastic lymphadenitis with dysproteinemia
(1163,1164). HHV-8 also may play a role in the pathogenesis
of primary CNS lymphoma (1165). HHV-8 rarely is associ-
ated with pars planitis (1166). HHV-8 encephalitis may
occur in immunosuppressed patients (1164).
Herpes B Virus
Of the nearly 35 herpesviruses isolated from nonhuman
primates, only one—herpes B virus of Old World mon-
keys—is highly pathogenic for humans (241,1167). The first
reported case of human infection caused by this virus oc-
curred in 1932 when a young physician, W.B., was bitten
by a monkey. He subsequently developed localized erythema
at the site of the bite, followed by lymphangitis, lymphadeni-
tis, and, eventually, transverse myelitis. He eventually died
of ‘‘respiratory failure.’’ Postmortem examination revealed
no definite evidence of infection, but tissue specimens were
obtained for further study by two independent research
groups. In 1933, Gay and Holden reported the discovery of
a virus in neurologic tissue from W.B. that, when injected
intradermally or intracranially into rabbits, produced a lethal
disease similar to that which had occurred in W.B. (1168).
The virus seemed to be similar to HSV and was called ‘‘W’’
by Gay and Holden after the first name of the patient from
whom the tissue was obtained. Working independently from
Gay and Holden with the same tissue, Sabin and Wright
(1169) discovered a filterable agent that they called ‘‘B
virus’’ after the last name of the patient from whom they
had received the tissue. These investigators were able to
isolate the virus from neural tissue, as well as from peripheral
organs. Subsequent intradermal or intracerebral injection of
the virus into rabbits produced the same lethal disease as
did injection of the ‘‘W’’ agent, although injection of the
virus by the same routes into a variety of other animals,
including mice, dogs, and guinea pigs, did not produce viru-
lent disease. In subsequent studies, Sabin emphasized the
similarity of the virus to HSV. Because latinization of viral
names was popular at this time, the virus acquired the name
Herpes simiae (241). This appellation is a misnomer, how-
ever, because nonhuman primates can become infected with
a host of unrelated herpesviruses, and the virus is formally
called Cercopithecine herpesvirus 1 (1167). In this chapter,
we refer to this virus as the herpes B virus.
3200 CLINICAL NEURO-OPHTHALMOLOGY
As is the case with other herpesviruses, herpes B virus
can become latent in an infected animal (1167). Thus, mon-
keys that do not appear to be clinically infected may never-
theless transmit latent virus to other animals and to humans.
In addition, viral reactivation may occur in animals with
latent infections. As is the case with HSV infections in hu-
mans, the most prominent factor associated with reactivation
of B virus in animals is stress, particularly the stress associ-
ated with the capture and shipping of animals from the wild
to captivity (241). Thus, Old World monkeys captured in
the wild and shipped to primate centers not uncommonly
develop vesicular lesions of the oropharynx, suggesting
herpes B virus reactivation similar to that which occurs with
HSV in humans.
Epidemiology
Herpes B virus is transmitted from animals to humans
primarily through the skin. The virus cannot penetrate intact
skin. Thus, a break in the skin is required for acquisition of
infection, and this is the reason that most cases of human
infection occur after an animal bite. The virus is indigenous
to Old World monkeys, and most reported cases of human
infection result from bites by rhesus (Macaca mulatta) or
cynomolgus (Macaca fascicularis) monkeys (1170). Fortu-
nately, only about 2–3% of infected animals excrete the
virus in their saliva. Thus, if a human is bitten by an animal,
the probability of infection is low. Similarly, although in-
fected animals can excrete the virus in tears, in vesicular
fluid, and perhaps in stool, the probability of human infection
occurring from contact with such material is negligible un-
less there is direct contact of the infected material with an
open wound.
A few cases of transmission of herpes B virus from ani-
mals to humans occur through the respiratory tract or by
needlestick injuries, and person-to-person transmission of
herpes B virus may also occur (1167). Nevertheless, casual
contact with an infected person generally is insufficient to
produce either symptomatic or asymptomatic infection
(241).
Pathogenesis and Pathology
Human infection with herpes B virus, as noted earlier,
occurs most often after a bite from an animal that is infected
with active or latent virus. Following the animal bite, replica-
tion of virus occurs at the local site of inoculation (241).
Usually, there is evidence of local inflammation with a
mononuclear infiltrate, followed by evidence of lymphangi-
tis and subsequent spread of inflammation to local lymph
nodes. The virus then spreads via the lymphatic system and
perhaps hematogenously to various organs of the body, in-
cluding the heart, liver, spleen, lungs, kidneys, and adrenals,
where it produces congestion and focal hemorrhagic ne-
crosis.
A prominent feature of human herpes B virus infection
is infection of the CNS. It is thought that the virus spreads
to the CNS via neuronal routes. Unlike HSV, which tends
to localize in the temporal and frontal lobes, herpes B virus
can affect any and all regions of the brain and spinal cord.
Histopathologic findings in the brain include hemorrhagic
foci, necrosis, and inflammatory changes consisting of peri-
vascular cuffing with mononuclear infiltrates (1171). Edema
and degeneration of motor neurons are prominent. Gliosis
and astrocytosis are late findings. Cowdry type A eosino-
philic intranuclear inclusions occasionally are seen in ad-
vanced cases (1172).
Clinical Manifestations
The clinical manifestations of human infection with
herpes B virus may be separated into four syndromes: (a)
asymptomatic infection, (b) disseminated disease following
an animal bite, (c) symptomatic infection acquired following
exposure to infected secretions by a respiratory route, and
(d) recurrent infection (241).
Asymptomatic human infection with herpes B virus prob-
ably is common in persons exposed to animals infected with
the virus, but it is rarely reported. More commonly described
is the development of disseminated disease following an ani-
mal bite (1167,1170). Following the bite of a monkey excre-
ting herpes B virus in the saliva, the patient develops a local-
ized vesicular lesion associated with erythema and edema
at the site of the bite. Lymphangitis subsequently occurs
with spread to regional lymph nodes and the development
of lymphadenopathy. Over the next 3–5 days, but occasion-
ally as late as 24 days after the bite, infected patients develop
fever, myalgia, vomiting, and cramping. Shortly thereafter,
they develop severe and rapidly progressive neurologic man-
ifestations. Meningeal irritation, nystagmus, and diplopia
may be the initial findings, but evidence of spinal cord in-
volvement rapidly develops and is characterized by altered
sensation of the limbs (i.e., hyperesthesia, paresthesias, or
both), followed by weakness, areflexia, and flaccid paralysis
(241). Some patients develop a brain stem encephalitis
(1173). Most patients ultimately develop a complete or al-
most complete transverse myelitis, and this is followed by
a progressive encephalitis characterized by decreased con-
sciousness, altered mentation, respiratory depression, sei-
zures, and, ultimately, death (1170). The time from onset of
symptoms to death varies considerably but may be as short
as 10–14 days. Patients who survive usually have severe
residual neurologic dysfunction (1174). Factors that influ-
ence the severity of disease and ultimate survival include
the age and immunologic status of the patient, the site of
the bite, and the quantity of the viral inoculum.
Although most cases of transmission of herpes B virus
infection from animals to humans occur from human expo-
sure to infected animal saliva by an animal bite, some cases
of apparent animal-to-human transmission occur by what
seems to be a respiratory route (1175). Initial symptoms in
patients with respiratory-transmitted herpes B virus infection
include fever, cough, coryza, laryngitis, and pharyngitis. The
symptoms progress rapidly to respiratory distress associated
with a radiographic picture of interstitial pneumonitis. Neu-
rologic manifestations subsequently develop, and some pa-
tients ultimately die despite supportive care.
A fourth manifestation of human infection with herpes B
 VIRUSES (EXCEPT RETROVIRUSES) AND VIRAL DISEASES
virus is recurrent infection. This occurs primarily in labora-
tory workers who regularly work with infected animals.
A case of apparent aseptic meningitis caused by herpes
B virus was reported by Scinicariello et al. (1176). The pa-
tient was a neurobiologist who had no history of an animal
bite and no recollection of any recent exposure to contami-
nated macaque tissues or cells, although numerous such sam-
ples were processed routinely in the laboratory where he
worked. The meningitis was not preceded by upper respira-
tory tract symptoms. Herpes B virus DNA was detected in
the patient’s CSF using PCR and nucleic acid probes, and the
patient was treated with both intravenous and oral antiviral
therapy with complete recovery. Davenport et al. (1173) also
reported a case of self-limited aseptic meningitis caused by
herpes B virus.
Diagnosis
The possibility of herpes B virus infection should be con-
sidered in any person who has contact with Old World mon-
keys, particularly rhesus and cynomolgus species. Further-
more, because person-to-person transmission of the virus
may occur, persons having intimate contact with animal
workers exposed to potentially infected animals should also
be considered to have herpes B virus infection in the appro-
priate clinical setting. The suspicion should be heightened
when there is historic or direct evidence of direct contact
with saliva, other body fluids, or tissue from a potentially
infected animal by bite, scratch, or laboratory accident (241).
Initial clinical findings suggesting herpes B virus infection
include a vesicular rash at a bite or scratch site with ipsi-
lateral regional lymphadenopathy. The progressive develop-
ment of neurologic symptoms and signs, particularly altered
sensation in the extremities, weakness, and hyporeflexia or
areflexia, makes the clinical diagnosis of herpes B virus in-
fection almost inescapable.
Serologic diagnosis of herpes B virus infection is ex-
tremely difficult because antigens designed to detect anti-
bodies specific to herpes B virus cross-react with antibodies
to HSV. Because of the relative uselessness of serologic
testing in diagnosing human infection with herpes B virus,
confirmation of such an infection usually is by recovery of
virus from vesicles, conjunctiva, saliva, or infected tissue.
Although the virus may be cultured from the CSF in patients
with neurologic manifestations, the yield is surprisingly low
considering the severity of the CNS disease. The use of DNA
amplification with PCR is the most rapid and accurate way
to diagnose herpes B virus infection (1176,1177).
Treatment and Prognosis
Although there are no controlled studies documenting the
efficacy of antiviral drugs in patients with herpes B virus
infection, the severity of the disease and its commonly fatal
outcome require that patients in whom herpes B virus infec-
tion is suspected or proven be treated immediately with an
antiviral drug, such as acyclovir or ganciclovir (241,
1167,1173). Indeed, early treatment of patients with proven
herpes B virus infection may be associated with a slowing of
progression of the disease and ultimate survival with normal
3201
neurologic function (1177). The physician confronted with
a patient with possible herpes B virus infection should obtain
the immediate assistance of an expert in infectious disease.
Almost all patients with symptomatic herpes B virus in-
fection develop a severe encephalomyelitis that ultimately
proves fatal (1169).
Prevention
The best way to prevent herpes B virus infection in hu-
mans is with careful attention to proper laboratory protocol
when handling potentially or definitely infected animals. We
are unaware of any vaccines that are useful in preventing
herpes B virus infection in humans (241,1175,1178), nor is
there any evidence that postexposure treatment with hyper-
immune serum or gamma globulin is of benefit in preventing
symptomatic human infection (1179).
PAPOVAVIRIDAE
The family Papovaviridae contains two genera: papillo-
mavirus and polyomavirus (1180). The name ‘‘papova’’ is
derived from the first two letters of each of three words:
papilloma, polyoma, and vacuolating agent. All papovavi-
ruses contain double-stranded, circular DNA that consists of
5,000–8,000 base pairs. These viruses replicate solely in the
nucleus of the host cell, and most are potentially oncogenic.
Papillomaviruses
Human papillomaviruses (HPVs) are widespread through-
out the population. They produce epithelial tumors of the
skin and mucous membranes, are associated with genital
tract malignancies (1180), and can be detected using PCR
(1181). HPVs appear to be involved in the genesis of both
benign and malignant neoplasms of the lacrimal sac epithe-
lium, with HPV type 11 associated with benign lesions and
HPV type 18 associated with malignancy (1182,1183). Con-
junctival HPV-related papillomas and carcinomas have been
described (1183–1188), and HPV may be involved in the
pathogenesis of pterygia (1189–1192).
Polyomaviruses
There are three known polyomaviruses: the BK and JC
viruses (named after the initials of the patients from whom
they were first recovered) and the simian vacuolating-40
(SV40) virus (1193).
BK Virus
Many children demonstrate serologic evidence of BK
virus exposure, and up to 70% of adults are seropositive
(1193). Peripheral leukocytes are a common site of BK virus
persistence (1194). Transmission is thought to occur via the
respiratory route in most cases (1195). BK virus can be iso-
lated from patients with certain brain tumors (1196), and
BK viral DNA can be detected not only in a variety of brain
tumors but also in other human neoplasms (1197,1198). In
addition, the BK virus can induce choroid plexus papillomas
and ependymomas in experimental animals (1197,1198).