Pediatric HSV Epithelial Keratitis презентация

morbidity that can cause significant vision loss due to its recurring nature. It is caused by the same 2 closely related viruses: herpes simplex virus type 1 (HSV-1) and herpes simplex virus type 2 (HSV-2). HSV-1 is the first member of the human herpes viruses (HHV-1) belonging to the subfamily Alphaherpesviridae. At least 80% of the world’s population has been exposed to HSV-1. Children with HSV keratitis pose a unique challenge to the clinician. The most serious concern in children is that they are susceptible to amblyopia (lazy eye) from corneal scarring that may occur. The virus is transmitted from human to human via secreted fluids and close contact with mucosal surfaces or abraded skin. Initial infection is usually asymptomatic and occurs in children younger than 5 years old. In cases of HSV-2, it is transmitted as the newborn passes through an infected birth canal. Ocular infection may occur directly through droplet spread or indirectly via neuronal spread from a nonocular site such as the oral mucosa.

stroma of the cornea. Manifestations can include cutaneous vesicles, blepharitis, conjunctivitis, epithelial keratitis (corneal dendritic ulcers), and stromal keratitis. Nonspecific signs of primary herpetic corneal infection include fever, malaise, and lymphadenopathy. When the virus gains access to the central nervous system, the virus becomes latent in the trigeminal ganglia (HSV-1 or varicella–zoster virus [VZV]) or in the spinal ganglia (HSV-2). Recurrent attacks occur when the virus travels peripherally via sensory nerves to infect target tissues in the eye. These attacks may be triggered by any of the following stressors: fever, ultraviolet light exposure, trauma, stress, menses, and immunosuppression.

neovascularization, and stromal keratitis. This disease usually occurs unilaterally, but bilateral infection, although not frequently seen, usually afflicts a younger age group and can be more severe. The corneal dendrites of herpes simplex infections are epithelial ulcers whose edges stain brightly with fluorescein and have terminal bulbs (Figure 19-1). Herpes zoster dendrites are raised lesions, do not have terminal bulbs, and do not stain well with fluorescein. Some ophthalmic findings of HSV keratitis are not directly caused by the viral infection itself, but instead relate to the immunologic response to the infection, such as chronic keratouveitis (inflammation within the anterior chamber of the eye) and disciform and necrotizing keratitis (cornea is filled with inflammatory cells and has neovascularization despite an intact surface).

rate of bilateral involvement in the largest series of infected children was 10% to 26%, which is higher than seen in adults. The Herpetic Eye Disease Study estimated that both epithelial and stromal keratitis recurred in 18% of patients during a follow-up period of 18 months. Age, sex, ethnicity, and nonocular herpes were not significantly associated with recurrences. However, the Herpetic Eye Disease Study was limited to patients 12 years or older. In different series of pediatric herpetic viral keratitis, recurrence rates ranged from 33% to 80%. Corneal scarring and ulcerations from recurrent herpetic keratitis can be visually debilitating and potentially necessitate surgical intervention with penetrating keratoplasty (corneal transplantation) or tarsorrhaphy (partial lid closure). The inflammatory response from herpetic keratitis leads to stromal scarring and opacification and tends to be more severe in children than adults. For younger children, especially under age 8, the corneal opacity and irregular astigmatism induced by the scars lead to visual deprivation and loss of vision. Even with antiviral therapy, corneal healing can take up to 1 month and will require continued ophthalmic care due to residual corneal scarring and risk of vision loss.

manifests as blepharoconjunctivitis (often with conjunctival ulceration) that heals without scarring (Fig. 4-15-3). The associated follicular conjunctivitis is often mistaken for adenoviral conjunctivitis (Fig. 4-15-4); up to a third of unilateral follicular conjunctivitis may be culture-positive for HSV.13–15 Other features include lid vesicles and conjunctival dendrites. Keratitis is rare, occurring in only 3–5% of cases, though severe bilateral disease can occur in atopic or immunocompromised patients.

menses, sunlight, irradiation, and emotional stress. Anecdotal reports have also implicated prostaglandin analogs, immunosuppression, and refractive surgery. Recurrent disease, estimated to occur in 27% of patients at one year and over 60% at 20 years, commonly causes keratitis (HSVK), though it can affect all parts of the eye.5 HSVK is broadly classifed into epithelial and stromal/endothelial keratitis. This classifcation is not only anatomical but is also important for understanding the pathophysiology of HSVK and for planning treatment.

fever) are thought to contribute
to risk of recurrence of non-ocular herpetic disease [ 9 ].
However, with correction for recall bias, the Herpetic Eye
Disease Study (HEDS) Group found that none of these fac-
tors were a signifi cant cause of recurrent ocular herpes [ 10 ].
However, a history of atopic disease has been associated
with recurrent herpetic eye disease, possibly secondary to
immunologic dysfunction [ 11 – 13 ]. Therefore, the practitio-
ner should inquire about personal and family history of con-
ditions such as asthma, eczema, and seasonal allergies.

foreign body sensation [ 24 ]. In children, photophobia is easily observed [ 26 ]. Pediatric HSV keratitis is typically unilateral; however, atopy and an altered immune system predispose to bilateral disease [ 7 ].
Diagnosis of HSV epithelial keratitis is typically based on
clinical fi ndings. Figure 11.2 shows a typical HSV dendrite.
The distinctive appearance and staining pattern of these
ulcers are important diagnostic points.

Fig. 1.17 a–d Features of an HSV dendritic (branching) fgure, visualized (a) without staining, (b and c) with fluoresceinsodium, (c and d) in time sequence, and (d) with rose bengal dye added. (a) Te fgure consist of two parts: a central corethat appears granular (long arrow) and a surrounding zone (short arrow) (cf. drawing). (b) Green-stained tear fluid is pooling within the central core. Te surrounding zone is elevated (dark). Within this zone, green fluid is pooling between protruding swollen/rounded cells (dark rounded dots, arrowhead)

more brilliantly green. As in (b), it is pooling within the central core and between the protruding swollen/rounded cells (arrowhead). So far, there is no fluorescein diffusion into the elevated surrounding zone. (d) A few minutes later, the elevated surrounding zone is stained brilliantly green (fluorescein diffusion). Rose bengal dye reveals patches of surface debris within the central core and a few rounded dots (arrowhead)

methods
that can be utilized to aid in the diagnosis of HSV epithelial
keratitis. Serum antibody testing can identify previous HSV
infection. It is important to note that viral samples for lab
testing should be collected prior to epithelial staining since rose bengal is toxic to HSV [ 29 ]. Collecting samples prior to staining will thus reduce false negative test results.

presented with 7 days of right eye pain, redness, and irritation. She was diagnosed with viral conjunctivitis by her primary care physician but did not improve. Slit-lamp examination with fl uorescein
revealed a dendritic epithelial defect with terminal bulbs (Fig. 10.3 ), and she was subsequently diagnosed with HSV epithelial keratitis. Treatment with 400 mg oral acyclovir suspension 4 times daily led to resolution of the dendrite with only minimal corneal scarring.

eye and exam demonstrated stromal infl ammation and haze without an epithelial defect (Fig. 10.4 ). She was diagnosed with immune stromal HSV keratitis , and was treated with a suppression dose of oral acyclovir and 0.1 % fl uorometholone drops 6 times daily, which were tapered off over 8 weeks as the stromal infl ammatory response improved. After resoution, she was maintained on a prophylactic dose of
oral acyclovir.

intervention [ 30 ], medication is utilized to speed
resolution, reduce corneal scarring, and diminish stromal
infl ammation. Since the epithelial ulcers are caused by actively
replicating virus, treatment targets the virus itself. Topical
antiviral drugs (trifluridine drops, vidarabine ointment [not
currently commercially available], or ganciclovir gel) have
been shown to be effective in resolving HSV epithelial kerati-
tis. However, instillation of eye drops in small
children may be difficult, and tear dilution from crying could
prevent an effective dose. Oral acyclovir thus provides an
important adjunctive treatment for pediatric HSV epithelial
keratitis, and may provide effective treatment without the use
of a topical antiviral [ 21 ]. See Table 11.1 for acyclovir dosage
considerations.

In children, the recommended dose
of oral acyclovir in epithelial keratitis is 12-40 mg/kg/day in
divided doses up to 40 kg, and the adult dose of 400 mg 5
times daily in children greater than 40 kg [2].

Interestingly, only topical antiviral medication has been
FDA approved for the treatment of HSV keratitis and only
for epithelial keratitis. Evidence-based oral antiviral treatment protocols have been developed for multiple forms of ocular HSV disease from retrospective studies as well as from the prospective studies conducted by the HEDS Group.

in combination with
topical treatment.

Epithelial HSV disease (dendritic ulcer, geographic ulcer)
is the result of viral replication, and is treated with a
topical antiviral agent (Table 15.9). Oral antiviral and
topical corticosteroid is not required.

in fact accelerate ulceration
[ 24 ]. However, topical corticosteroids play a role in the treat-
ment of HSV stromal keratitis. Stromal keratitis is discussed
in the next section. Some clinicians recommend debridement
of infected epithelial cells to enhance resolution. Historically,
corneal debridement has been described as a method to reduce
the amount of active virus in the epithelium. However, debride-
ment may be less effective than antiviral therapy and may not
signifi cantly improve outcome of antiviral therapy [ 32 ].
Additionally, corneal debridement is diffi cult in children, and
may increase discomfort.

keratitis can recur. After an epithelial ulcer resolves, a
faint stromal scar may remain. Recurrent HSV dendritic
ulcers may recur near the scar. Epithelial recurrences increase
the risk of HSV stromal keratitis, an immune-mediated dis-
ease process. Recurrence of HSV keratitis is higher in chil-
dren and is a major management concern [ 21 ]. Thus,
monitoring of children with periodic follow-up examinations
and educating the parents for signs of recurrence are essen-
tial.

inactive HSV antigen in the corneal
stroma [ 6 ]. However, complex presentations with mixed pat-
terns of anterior corneal disease and corneal scarring from
multiple recurrences are possible [ 24 ]. Simple HSV stromal
keratitis may present with single or multifocal sub-epithelial
infl ammatory infi ltrates.

l-
trates and results in a disease presentation known as interstitial keratitis. Figure 11.3 demonstrates an active interstitial keratitis with stromal infi ltrates and vascularization.

topi-
cal corticosteroids and oral antivirals. The topical corticoste-
roid is necessary to treat the stromal infl ammation, and the
oral antiviral treats any active viral disease in addition to a
putative contribution in preventing recurrence

after the fi rst episode. However, longitudinal treatment throughout the amblyogenic period may be required to prevent visually debilitating scarring in the visual axis and resultant amblyopia. Corticosteroid should be tapered to the
minimum amount necessary to control infl ammation.

keratitis since it has
been FDA approved for long-term treatment (at the 1 g/day
suppressive therapy dose for genital herpes) [ 33 ]. Valacyclovir
is a pro-drug of acyclovir that has an ester moiety that is
removed by esterases to result in the active acyclovir. As a
pro-drug of acyclovir, valacyclovir has greater bioavailability
and would theoretically be expected to have a similar side
effect profi le. Famciclovir has also been approved for long-
term suppressive therapy of genital herpes (at 250 mg twice a
day), so it may also be considered for HSV stromal keratitis
in older teenage patients [ 34 ]. However, famciclovir is not
FDA approved for children.

disease.

In cases with concomitant epithelial disease, topical treatment is generally added for the fi rst 2 weeks.

For stromal disease (e.g. disciform keratitis), topical steroid (1% prednisolone phosphate four times daily), in conjunction with topical antiviral cover, reduces recovery time by 68% with no increased risk of recurrence at 6 months.
• There is no additional effect of oral acyclovir over topical steroid and F3T when treating stromal keratitis.
• After epithelial HSV a 3-week course of oral acyclovir (400 mg 5 times a day) does not prevent stromal disease in the subsequent year.

• Prophylactic treatment with acyclovir (400 mg bd) reduces epithelial recurrences and stromal recurrences in patients with prior stromal disease by about 50% over 12 months. Prophylactic treatment is usually restricted
to patients with bilateral disease, prior HSV keratitis in atopes, or the immunosuppressed, especially following
corneal surgery.

(skin, eye, and/or mouth), disseminated
herpes affecting internal organs, and central nervous system
infection (encephalitis). An infected infant may display sev-
eral of these features. Ocular herpes in the newborn typically
appears as periorbital skin vesicles, blepharoconjunctivitis,
keratitis, anterior uveitis, chorioretinitis, and congenital cata-
racts [ 3 , 39 ]. Importantly, a dilated fundus examination
should be performed in any neonate with suspected HSV infection. Since herpes infections may resemble other neona-
tal infections, laboratory tests (e.g., fl uorescein antibody tests,
herpes culture, or PCR testing) should be performed in all
cases of suspected neonatal herpes [ 28 ]. While awaiting lab
results, the newborn should be empirically treated with intra-
venous acyclovir.

antiviral therapy is generally good.
However, mortality is higher in newborns with disseminated
infection or CNS disease [ 28 ]. Visual outcome is poorer
when corneal herpetic disease causes scarring. Infants must
also be monitored closely for evidence of recurrent disease.
Infants with recurrent HSV keratitis are typically followed
longitudinally by an infectious disease specialist.
Additionally, longitudinal follow-up by a pediatric ophthal-
mologist is important due to the risk of amblyopia develop-
ment associated with recurrent HSV keratitis. If there is
recurrent neonatal ocular HSV infection, higher oral doses of
acyclovir may be necessary.