Ocular Immunology and Inflammation

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Pediatric Pars Planitis: A Review

Sana Khochtali, Pinar Ozdal, Abdulrahman F. AlBloushi, Wijdène Nabi &

Moncef Khairallah

To cite this article: Sana Khochtali, Pinar Ozdal, Abdulrahman F. AlBloushi, Wijdène Nabi
& Moncef Khairallah (2023) Pediatric Pars Planitis: A Review, Ocular Immunology and
Inflammation, 31:10, 1915-1929, DOI: 10.1080/09273948.2023.2279683

To link to this article: https://doi.org/10.1080/09273948.2023.2279683

Published online: 17 Nov 2023.

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OCULAR IMMUNOLOGY AND INFLAMMATION
2023, VOL. 31, NO. 10, 1915–1929
https://doi.org/10.1080/09273948.2023.2279683

INVITED REVIEW

Pediatric Pars Planitis: A Review

Sana Khochtali, MDa, Pinar Ozdal, MDb, Abdulrahman F. AlBloushi, MDc, Wijdène Nabi, MDa,
and Moncef Khairallah, MDa
a
Department of Ophthalmology, Faculty of Medicine, Fattouma Bourguiba University Hospital, University of Monastir, Monastir, Tunisia; bService of
Uveitis and Retinal Diseases, Ankara Ulucanlar Eye Research Hospital, Ankara, Turkiye; cDepartment of Ophthalmology, College of Medicine, King
Saud University, Riyadh, Saudi Arabia

ABSTRACT ARTICLE HISTORY

Purpose: To provide an overview of pediatric pars planitis. Received 19 September 2023
Methods: Narrative literature review. Revised 29 October 2023
Results: Pars planitis refers to the idiopathic subset of intermediate uveitis in which there is vitritis along Accepted 31 October 2023
with snowball or snowbank formation occurring in the absence of an associated infection or systemic KEYWORDS
disease. It is thought to be a T-cell mediated disease with a genetic predisposition. Pars planitis accounts Intermediate uveitis; macular
for 5–26.7% of pediatric uveitis cases. Presentation is commonly bilateral but asymmetric, often with edema; pars planitis;
insidious onset of floaters and blurred vision. Although pars planitis is known to be a benign form of pediatric uveitis; snowballs
uveitis in most cases, severe complications secondary to chronic inflammation may arise, with cystoid
macular edema being the most common cause of visual morbidity. Mild vitritis in the absence of
symptoms, vision loss, or macular edema may be observed. Patients with severe vitritis and/or associated
vision-threatening complications require prompt aggressive treatment. A stepladder approach including
corticosteroids, immunosuppressive agents, anti‑tumor necrosis factor‑alpha and pars plana vitrectomy
and/or laser photocoagulation is the most commonly used method for treatment of pars planitis.
Conclusion: Timely diagnosis and adequate treatment of pediatric pars planitis and associated compli­
cations are crucial in order to improve visual outcomes.

According to the Standardization of Uveitis Nomenclature (SUN) Pathogenesis and pathology

criteria, uveitis is classified on the basis of the primary anatomic
The pathogenesis of pars planitis is not completely understood
site of inflammation into anterior uveitis, intermediate uveitis
and remains to be elucidated. This seems to be an immunolo­
(IU), posterior uveitis, and panuveitis. IU is defined as an intrao­
gically mediated disease, most likely a T-cell mediated reaction
cular inflammation mainly focused on the vitreous and peripheral
to endogenous antigen of unknown source, leading to a clinical
retina, with an absence of choroiditis or retinitis. The presence of picture of vitreous inflammation and peripheral vasculitis.10,11
peripheral vascular sheathing and macular edema does not T cells account for up to 95% of all cell types in the vitreous of
change the classification. The diagnostic term pars planitis is patients with pars planitis, and most of these cells are CD4+.
used only for that subset of IU where there is snowball or CD4+ T cells that express CD69, an activation marker, are
snowbank formation occurring in the absence of an associated found in aqueous humor and blood of patients with pars
infection or systemic disease.1 Pars planitis should therefore be planitis.12,13 The role of CD8+T cells and B cells in the patho­
considered as an anatomic subcategory of idiopathic IU (negative genesis of pars planitis is not clear.10 Pars planitis is associated
work-up). If there is an associated infection such as tuberculosis with an increased frequency of effector-memory CD57+ T cells.
(TB), syphilis or Lyme disease or an underlying systemic disease CD57+ T cells are considered to be correlated with late immune
such as sarcoidosis or multiple sclerosis (MS), then the term IU responses.14 After T cells, macrophages are the second most
should be used.2,3 IU accounts for 0.9 to 22.9% of all uveitis common cells present.15 IL-6 was found to be elevated in the
patients, and up to 41.7% of pediatric uveitis cases.4 Most cases vitreous of patients with active intermediate and posterior uvei­
of IU in children occur without any underlying disease, and tis. Whereas IL-1, TNF-alpha, and IL-2 were not detected.16
therefore are classified as idiopathic IU or pars planitis.5 Pars There is also a genetic predisposition for the pars planitis.
planitis is an important diagnosis to recognize in children, as A number of studies described the contribution of the human
studies have demonstrated that children are at risk for vision leukocyte antigen (HLA) and several other genes in addition to
loss, and a shorter time period from symptom onset to diagnosis those of the HLA in the pathogenesis of pars planitis.
and treatment is correlated with improved visual outcomes.6–9 Associations between pars planitis and HLA‑DR2, ‑DR15,
In this review, we provide an overview of the pathogenesis, ‑B51 and ‑DRB1 × 0802 haplotypes have been described sug­
epidemiology, clinical and imaging manifestations, complications, gesting an immunogenetic predisposition.17–19 Patients who
diagnosis, treatment, and prognosis of pediatric pars planitis. were HLA‑DR15 positive were reported to have systemic

CONTACT Moncef Khairallah, MD [email protected] Department of Ophthalmology, Faculty of Medicine, Fattouma Bourguiba University Hospital,
Monastir 5019, Tunisia
© 2023 Taylor & Francis Group, LLC
1916 S. KHOCHTALI ET AL.

findings of other HLA‑DR15 related disorders such as MS, abrupt loss of vision owing to acute vitreous hemorrhage or
optic neuritis, and narcolepsy, suggesting a common genetic retinal detachment.38,39 Cases of pediatric pars planitis may be
background.20 In Mexican Mestizos, more severe inflamma­ asymptomatic and diagnosed by chance during a routine eye
tion has been associated with HLA‑B51 in female patients and examination. Children may also present with school problems
with HLA‑DRB1 × 0802 in male subjects.19 Smith et al noticed by teachers or parents, strabismus, or altered red
reported race and ethnicity to be associated with reflex.8,33
a predisposition to different patterns of uveitis, as well as
pars planitis. They found that in their pediatric population
Signs
the prevalence of pars planitis was significantly lower in
Hispanic children as compared to non‑Hispanics (9.6% versus The anterior chamber may be quiet or may have signs of
19.2%).21 inflammation (28–50%).33,35,40,41 There may be mild ante­
Histologic studies in eyes with pars planitis show con­ rior chamber cells and flare, small keratic precipitates, and
densed vitreous, fibroblasts, lymphocytes, and lymphocyte even rarely posterior synechiae, usually involving the infer­
cuffing of the peripheral retinal veins. Snowbanks and snow­ ior iris.35,40 Peripheral corneal endotheliopathy has been
balls consist of a fibrovascular layer containing mononuclear reported in patients with pars planitis. Corneal examination
leukocytes and fibrocyte-like cells, as well as vitreous collagen, reveals opacification of the posterior cornea in an inferior
Müller cells, and fibrous astrocytes.22 location (Figure 1). There may be keratic precipitates line­
arly arranged at the junction of the edematous and non-
edematous cornea, suggesting an underlying autoimmune
Epidemiology disease, similar to the phenomenon of corneal allograft
IU is a rare disease, with an estimated incidence of 1.4–2/ rejection.42,43 Band keratopathy has been reported in chil­
100.000. The prevalence is estimated to be 4–5.9/100.000. It dren with IU, as may occur in any type of chronic pediatric
accounts for 0.9–22.9% of uveitis patients in general ophthal­ uveitis. The presence of any of these anterior findings should
mology practice and 10–41.7% of pediatric practice.4,23–25 prompt a detailed dilated posterior segment examination,
Even with a full diagnostic work-up, a large proportion of IU including depressed peripheral retinal examination, not to
cases remain idiopathic. A subset of idiopathic IU with evi­ miss the diagnosis of pars planitis.
dence of snowballs or snowbanking matches the definition of Vitritis with anterior predominance is a characteristic fea­
pars planitis. Pars planitis accounts for 5 to 26.7% of uveitis ture of IU, and it is typically described as vitreous cells and
across various pediatric populations.26–32 In a retrospective haze ranging from trace to 4 + . It may become so dense as to
study, Ozdal et al. observed pars planitis as the leading cause obscure the retina entirely, making difficult for one to exclude
of pediatric uveitis with a rate of 24%.32 Whereas Soylu et al.,29 the diagnosis of posterior uveitis.40 Vitreous snowballs typi­
AlBloushi et al.28 and Paroli et al.31 reported slightly lower cally are globular yellow-white inflammatory aggregates, and
prevalence rates for pars planitis (8.9%, 11.2%, and 18.7% are found in the midvitreous and inferior periphery. They lie
respectively). Paroli et al. reported that pars planitis was close to the retina, but are not in contact with it (Figure 1).
the second most common cause of uveitis in Italian children They have been reported to be present in up to 100% of
following juvenile rheumatoid arthritis and that the occur­ affected eyes.
rence of pars planitis was highest in children aged between 6 Snowbanking is the hallmark of pars planitis. The snowbanks
and 10 years.31 Nikkhah et al. reported that the mean age at have a white or yellowish-white appearance and typically cover
diagnosis was 7.8 years.7 Similarly, a mean age of 9.2 years at the pars plana, starting inferiorly and migrating superiorly
the time of diagnosis has been stated by Romero et al..33 The (Figure 1). If snowbanking is chronic, it can evolve into
gender distribution is controversial. Male predominance has a fibrotic, cyclitic membrane, leading to vitreous traction and
been reported in different studies.7,33,34 Nikkhah et al. found retinal detachment or retinoschisis. This peripheral snowbank­
a marked male predominance with a male to female ratio of 5 ing is best seen either with the Goldmann three-mirror lens or
to 1.7 Pediatric pars planitis usually affects both eyes (80%); with a 20+ diopter lens and scleral indentation. Snowbanks have
however, it may demonstrate asymmetrical involvement and been observed in around 60‑65% of cases, and their presence
the less affected eye can show only a few cells in the vitreous.33 seems to be associated with worse visual outcome.41,44
The vitreous may show degenerative changes with fiber-
like cylindric condensations of coarse vitreous strands
Clinical features (Figure 1). Posterior vitreous detachment is common.
Children with pars planitis may present with vitreous
Symptoms
hemorrhage.38 Peripheral retinal vascular sheathing, primar­
Children with pars planitis often present with minimal symp­ ily involving venules is a common finding, occurring in 10–
toms, which may include floaters or blurred vision.35,36 Onset 36% of patients with pars planitis. Retinal vasculitis may be
is typically insidious and bilateral but asymmetrical in both subtle ophthalmoscopically; it is best appreciated by fluor­
eyes. Other less common symptoms related to associated ante­ escein angiography (FA). A detailed examination of the
rior segment inflammation include pain, photophobia, and red fundus shows the absence of retinal or choroidal lesion.
eye.35 In more severe cases, visual acuity (VA) may be signifi­ Cystoid macular edema (CME) is the major cause of visual
cantly reduced due to aggregation of floaters in the vitreous or loss both at early onset and in the long-term follow-up. It
due to macular edema.37 Sometimes, patients present with can be suspected clinically and confirmed by optical
 OCULAR IMMUNOLOGY AND INFLAMMATION 1917

Figure 1. (a) Fundus photograph showing snowballs inferiorly in a 10-year-old child with pars planitis. (b) Fundus photograph showing inferior snowbanking over the
pars plana and the peripheral retina. (c) Fundus photograph showing snowballs and vitreous veils inferiorly in an 11-year-old girl with pars planitis. (d) Slit-lamp
photograph in a 10-year-old child with unilateral pars planitis showing peripheral corneal endotheliopathy (arrow) and localized inferior posterior synechiae.

coherence tomography (OCT) and FA. Optic disc edema and FA has become the gold standard for the evaluation and
hyperemia have been reported in up to 71% of eyes with monitoring of retinal vasculitis associated with uveitis, includ­
pediatric pars planitis and might be more common than in ing pars planitis, by showing fluorescein dye leakage from
adult cases.28 compromised retinal vessels. It is also a useful tool for detect­
ing peripheral retinal ischemia, neovascularization, CME,
macular ischemia, and optic disc hyperfluorescence. Ultra-
widefield FA provides a better assessment of inflammatory
Ocular imaging
activity in IU by revealing more information about the pat­
Multimodal imaging, including conventional and modern terns and degree of vascular leakage both in the periphery and
techniques, is essential to comprehensively evaluate and follow the posterior pole (Figure 3). As most cases of IU present with
pediatric pars planitis. Slit-lamp photography enables docu­ peripheral signs, ultra-widefield angiography may be used over
mentation and follow-up of anterior segment changes that conventional angiography as the investigation of choice.46,47
may accompany pars planitis. Indocyanine green angiography has no clinical benefit in
Digital color fundus photography allows documentation pars planitis and may only be used to rule out choroidal
of baseline fundus changes, and helps to assess disease pro­ inflammation in challenging cases.44
gression and response to treatment during follow-up. Recent OCT is a very useful diagnostic technique for evaluation
advances in wide- and ultra-widefield imaging techniques of retinal layers, and retinal and macular pathologies related
have significantly contributed to better assessment of the to intraocular inflammation. The use of OCT as a screening
retinal periphery. Peripheral changes that can be documented tool has been proposed for the initial work-up of children
by color fundus photography include snowballs, snowbanks, with pars planitis to identify possible macular edema which
peripheral vitreous tractional membranes, retinal vascular influences disease-management decisions and visual
sheathing, retinoschisis, and retinal detachment. Color fun­ prognosis.48 OCT imaging is the gold standard for the eva­
dus photography can also help to document macular changes luation of uveitic macular edema (Figure 2). It enables non-
including macular edema, epiretinal membrane, atrophic invasive, objective, precise detection, classification (cystoid,
changes, and optic disc edema. Fundus photographs taken diffuse, serous retinal detachment), and quantification of
at baseline and at follow-up visits allow objective measure­ macular thickness. It is also very useful in evaluating quali­
ment and direct comparison of changes in vitreous haze tative structural changes, monitoring the therapeutic
(Figure 2).45 response, and determining visual prognosis. The most
1918 S. KHOCHTALI ET AL.

Figure 2. (a) Fundus photograph of the right eye of a 10-year-old boy with pars planitis showing 3+ vitreous haze. (b) Initial OCT revealing cystoid macular edema
(initial visual acuity: 20/400). (c) Fundus photograph taken one year after initiation of methotrexate and adalimumab associated with a short course of corticosteroids
showing a complete resolution of vitreous haze. (d) Follow-up OCT showing a complete resolution of macular edema (final visual acuity: 20/20).

superficial and deep retinal layers as well as greater heteroge­

neity of choriocapillaris perfusion, indicating impairment of
the macular microvasculature. These changes could be seen
even in the absence of macular edema.53
A prominent feature of uveitic CME on OCTA is the
presence of well-delineated cystoid spaces completely devoid
of flow, mostly involving the deep capillary plexus (DCP).
Associated qualitative perifoveal microvascular changes
include grayish nonperfused/hypoperfused areas, rarefied
capillaries, architectural disorganization, and dilated capil­
laries, with more severe involvement of the DCP in compar­
ison with the superficial capillary plexus.51,52,54,55 Severe
quantitative microvascular changes in the DCP in eyes
with inflammatory CME were found to be associated with
a poorer baseline VA, a longer duration of macular edema
Figure 3. Ultra-widefield fluorescein angiogram of the right eye of a child with
pars planitis showing diffuse retinal capillary leakage in the posterior and per­ (>6 months), and a higher central retinal thickness.51
iphery, as well as staining and leakage from retinal veins. Note the presence of Resolution of uveitic CME on OCT may be associated with
cystoid macular edema and optic disc hyperfluorescence. a complete recovery of the normal pattern of retinal capil­
lary plexuses or persistence of areas of capillary rarefaction
important OCT biomarkers for disease severity and prog­ or hypoperfusion on OCTA. The persistence of impaired
nosis include central macular thickness, macular edema pat­ foveal blood flow after the resolution of uveitic CME has
tern, ellipsoid zone integrity, and disorganization of retinal been associated with a worse final VA.51,52 Wide-field
inner layers. OCT is also an essential tool for detecting OCTA is a non-invasive tool for the assessment of periph­
uveitic macular changes other than macular edema, includ­ eral retinal ischemia in IU.56
ing vitreous punctate spots indicative of vitreous cells, epir­ Ultrasonography is a valuable instrument providing addi­
etinal membrane formation, vitreomacular traction, foveal tional information regarding vitreous and retina in uveitis
atrophy, and lamellar or full-thickness macular hole. cases with poor visualization of the fundus. The conventional
Macular atrophy is associated with longer disease duration ultrasound device uses a frequency in the range of 8-10 MHz
and worse VA.49–52 for standard examination. It can provide useful information on
OCT angiography (OCTA) is a new, non invasive, dyeless the vitreous, retina, choroid, and optic nerve. While higher
imaging modality that provides a three-dimensional mapping frequencies such as 20 MHz may be more useful to detect the
of the retinal and choroidal microvasculature. Reports of presence of macular edema. Ultrasound biomicroscopy
OCTA imaging in pediatric IU are scarce. In adult patients (UBM) employs higher frequencies than ultrasonography
with IU, OCTA imaging shows reduced vascular density in the (35–100 MHz), providing high-resolution images of the pars
 OCULAR IMMUNOLOGY AND INFLAMMATION 1919

plana region. It can detect snowbanking, cyclitic membranes, potential cause of permanent visual loss, particularly in
peripheral vitreous membranes and vitreoretinal tractions. younger children, is amblyopia.6,62 Therefore, amblyopia ther­
UBM is also useful for monitoring the response to apy should be begun promptly to restore vision in children
treatment.44,45,57,58 with pars planitis.
Vitreous hemorrhage is a well-recognized ocular complica­
tion in children with pars planitis, with a prevalence estimated
Complications between 3% and 9% of children.6–8,28,38 Felder and Brockhurst
have described that the vitreous hemorrhage usually occurs
Childhood pars planitis may lead to visual loss due to compli­
secondary to neovascularization.63 The neovascularization
cations and permanent damage to ocular structures, especially
may occur in one of three forms: peripheral snowbank neo­
if the diagnosis and treatment are delayed.21,24 Compared with
vascularization, optic disc neovascularization, and neovascu­
the adult population, pars planitis during childhood is typically
larization elsewhere in the retina. Vitreous hemorrhage may
associated with a higher frequency of sight-threatening com­
also occur in association with retinal tears and detachments.
plications (Table 1).9 This is attributed to the chronic and
A previous study has reported that children with pars planitis
asymptomatic nature of the disease, particularly among
are more likely to have vitreous hemorrhage than adults.63 The
younger children, which can delay the diagnosis and
reason for an increased prevalence of vitreous hemorrhage in
management.28 Pars planitis in children can be discovered
pediatric pars planitis patients remains speculative. One of the
incidentally during a routine eye examination, highlighting
most obvious explanations is the delayed presentation, espe­
the importance of ongoing eye health surveillance in children.
cially in preverbal children with late‑stage disease. A second
Previous studies have demonstrated that the most fre­
possibility is that children may exhibit a more severe inflam­
quently reported complication of pediatric pars planitis is
matory and/or fibrovascular response.64
CME, with an estimated incidence ranging between 13.1%
Epiretinal membrane formation was found to be directly
and 57%.6–8,28,33,48,59–61 Other studies found cataract as the
related to disease chronicity and was reported to occur in up
most common complication, with an estimated incidence ran­
to 14% of children with pars planitis.6,7,28,33 Retinal detach­
ging between 13.5% and 47.5%.7,33,61 Other reported compli­
ment, either tractional, rhegmatogenous, or exudative, has
cations include ocular hypertension/glaucoma, band
been described as an uncommon manifestation of pars pla­
keratopathy, optic disc edema, retinoschisis, vitreous hemor­
nitis in children. The reported incidence varied from 0.9% to
rhage, epiretinal membrane, retinal detachment, hypotony,
10%.6–8,28,33,48,61 Malinowski et al.39 found that visually sig­
rubeosis iridis, retinal neovascularization, and vasoprolifera­
nificant cataracts are associated with a higher risk of devel­
tive tumors.6–8,28,33,48,59–61 In a large series by AlBloushi et al.28
oping retinal detachment in patients with pars planitis. The
the most common complication of pediatric pars planitis was
speculative explanation of this association can be attributed
elevated intraocular pressure that occurred in 52% of children
to the presence of more aggressive inflammation that induces
followed by cataract (32.8%), CME (13.1%), glaucoma (6.8%),
cataract, disturbance of the vitreous base and development of
and papillitis (6.3%). The leading cause of visual loss in chil­
retinal detachment. Moreover, it has been found that the risk
dren with pars planitis is macular edema.6,7,28,33,48,61 Recently,
of retinal detachment decreased over time in patients with
Navarrete et al.48 reported that CME in children with pars
pars planitis. Interestingly, rhegmatogenous retinal detach­
planitis is associated with higher risks of other ocular compli­
ment (RRD) associated with pars planitis has been shown to
cations, a more frequent use of immunomodulatory therapy,
have a large number of peripheral retinal breaks, mainly
and a lower remission rate.
composed of round holes, and a greater extent compared to
Glaucoma is another key sight-threatening complication
primary RRD cases.65 It has been shown that the primary
that could be related to the uveitis itself or due to concomitant
anatomic outcome of RRD repair was lower in patients with
corticosteroid use and has been reported in up to 52% of the
pars planitis compared with primary RRD cases. Moreover,
affected eyes.6–8,28,33,61 Prompt controlling of inflammation
RRD associated with pars planitis carries a higher risk of
and limiting the use of corticosteroids can confer protection
proliferative vitreoretinopathy than primary RRD cases.65
against ocular hypertension and glaucoma.28 Another
Exudative retinal detachment (ERD) is another rare finding
reported in children with pars planitis.48 Peripheral retinal
Table 1. Ocular complications in children with pars planitis. elevation secondary to ERD or schisis may develop after sev­
Complications Frequency eral years of active uveitis and rarely needs an intervention.66 It
Macular edema 13.1–57%6–8,28,33,48,59–61 has been hypothesized that the elevation of the peripheral
Cataract 13.5–47,5%7,33,61 retina occurs due to vascular abnormalities caused by fluid
Intraocular hypertension 52%28
Glaucoma 6.8–52%6–8,28,33,61 leakage in the retina from dilated retinal vessels. In addition to
Optic disc edema 6.3–71%28,59 the exudative mechanisms of peripheral retinal elevation, trac­
Epiretinal membrane Up to 14%6,7,28,33 tion mechanisms have been described. Traction is hypothe­
Retinal detachment 0.9–10%6–8,28,33,48,61
Retinoschisis Up to 23.3%33 sized to occur due to the contraction of the snowbanking,
Retinal neovascularization 1–6%6,60 causing both tangential and radial traction on the peripheral
Vasoproliferative tumor 3%48 retina, leading to peripheral retinal elevation.67 Retinoschisis is
Vitreous hemorrhage 3–9%6–8,28,38
Band keratopathy Up to 17%6–8,28,48 not uncommon in patients with pars planitis and is described
Hypotony 0.9%8 in up to 23.3% of children.33 Julia et al.66 described that
Amblyopia 17%6,7 retinoschisis is typically bilateral, inferior, and adjacent to
1920 S. KHOCHTALI ET AL.

Table 2. Criteria for the diagnosis of pars planitis (adapted from the SUN working group classification criteria for pars planitis (3)).
1-Vitritis : vitreous cells and/or vitreous haze
2-Evidence of snowballs or snowbanks
3-No evidence of chorioretinal inflammatory lesions or posterior vascular sheathing
4-No occlusive retinal vasculitis in the posterior pole or mid-periphery
(but the presence of peripheral areas of retinal capillary non-perfusion on wide-field fluorescein angiography is compatible with the diagnosis of pars planitis)
5-Exclusion of specific etiologies of intermediate uveitis with snowballs or snowbanks mainly syphilis, sarcoidosis, multiple sclerosis, tuberculosis, and Lyme disease

a snowbank. Examination of eyes during pars plana vitrectomy Masquerade syndromes are important to consider in young
revealed a tractional component in all cases, with retinal ves­ patients with vitritis. In children, neoplastic masqueraders
sels pulled toward the snowbank, suggesting that mechanical mainly include retinoblastoma. Diffuse infiltrating retinoblas­
forces play a role in the development of schisis. Furthermore, toma is a rare unilateral sporadic retinoblastoma occurring in
schisis may develop and progress in patients with both con­ older children that has a propensity to masquerade as uveitis or
trolled and uncontrolled uveitis. Vasoproliferative tumors endophthalmitis. Clumps of white vitreous seeds are often
have been reported to occur in 3% of children with pars associated with white deposits on the corneal endothelium
planitis.48 On the other hand, IU, mainly pars planitis, is the and pseudo-hypopyon. There is no well-defined retinal mass
most common cause of secondary retinal vasoproliferative on initial examination but the retina is typically diffusely
tumors in children, accounting for 28% of cases. thickened.72,73 Other non-neoplastic masqueraders in children
Vasoproliferative tumors can be unilateral or bilateral and include intravitreal hemorrhage, retinitis pigmentosa, familial
seem to be related to the severity of IU.68 exudative vitreoretinopathy, other retinal dystrophies, intrao­
Boer et al.59 reported that optic disc edema was the most cular foreign body, and retinal detachment.
common complication observed in children with pars planitis A work-up should be performed in all children with pars
(71%). It was previously suggested that optic disc edema is planitis to rule out alternative diagnoses. It mainly includes
more frequently seen in children than adults with intraocular a clinical examination by the pediatrician/internist, a complete
inflammation.69 The long-term risk of optic disc edema in pars blood count, a C-reactive protein, an erythrocyte sedimenta­
planitis has not been elucidated, but it has been suggested that tion rate, syphilis serology, a chest X-ray, a tuberculin skin test
prolonged axonal stasis may lead to optic atrophy and subse­ and/or interferon-gamma releasing assay (IGRA), and serum
quent vision loss.70 However, the risk of prolonged optic disc angiotensin-converting enzyme (ACE).4,37 Other oriented
edema in children with pars planitis needs further tests may be ordered if needed. Brain magnetic resonance is
investigation. not routinely recommended.3,74 It is performed when MS is
Band keratopathy has been reported in up to 17% of chil­ suspected or before initiating anti‑tumor necrosis factor‑α
dren with pars planitis secondary to concurrent anterior seg­ (anti-TNF- α) agents.44
ment inflammation.6–8,28,48 Although band keratopathy can IU accounts for less than 2% of syphilitic uveitis. In this
occur at any age, it is considered by many to be the hallmark setting, vitritis may be associated with pearl-like precipitates,
of pediatric uveitis. The high prevalence of band keratopathy optic disc edema/optic neuritis and retinal vasculitis.75,76
in children with uveitis may reflect the chronicity and severity Serology includes non-treponemal tests including Venereal
of many forms of uveitis seen in this age group, including pars disease research laboratory (VDRL), Rapid plasma reagin
planitis. (RPR) tests and direct treponemal tests including Treponema
pallidum particle agglutination (TP-PA), Treponema pallidum
Hemagglutination (TPHA) and Fluorescent treponemal anti­
Diagnosis and differential diagnosis
body absorption test (FTA-abs).75
The pars planitis has been defined by the Standardization of IU is a possible manifestation of ocular TB. Vitritis may be
Uveitis Nomenclature (SUN) Working Group in 2005 as associated with snowballs and retinal vasculitis.77
a subset of IU characterized by the presence of snowbanks or Snowbanking is a rare finding in tubercular IU.78
snowballs in the absence of an associated infection or systemic Tuberculosis should always be excluded. A chest X-ray and
disease.1 According to this definition, the term pars planitis a tuberculin skin test and/or IGRA should always be
refers not only to an anatomic subtype of IU, but also to an performed.
etiologic subtype, implicating that there is no identified asso­ Toxocariasis should be considered as a possible etiology in
ciated disorder (idiopathic).71 More recently, the SUN children with unilateral IU. Peripheral toxocara granuloma
Working Group has agreed that key criteria for pars planitis may be difficult to distinguish from a snowbank lesion. The
include unilateral or bilateral IU with either snowballs in the presence of traction bands is highly suggestive of the
vitreous or snowbanks on the pars plana, and that key exclu­ diagnosis.79 Toxocariasis serology should be included in the
sions include multiple sclerosis (MS), sarcoidosis, and laboratory investigations in children with unilateral IU.
syphilis.3 Furthermore, the group recognized that eyes with Although Lyme disease is a rare cause of uveitis even in
pars planitis might show peripheral retinal vascular sheathing endemic countries, IU is a common anatomic form of Lyme-
and non-perfusion (more easily seen on wide-field FA) but associated uveitis and is usually associated with retinal vascu­
should not have a posterior pole or mid-peripheral occlusive litis. It has been described in children and adolescents with
retinal vasculitis3 (Table 2). A practical approach for the diag­ Lyme arthritis. Diagnosis is challenging as ocular findings are
nosis of pars planitis in children is shown in Figure 4. nonspecific, a positive serology may be coincidental, and
 OCULAR IMMUNOLOGY AND INFLAMMATION 1921

Figure 4. A practical approach leading to the diagnosis of pediatric pars planitis.

testing gives more false positive than true positive results. IU is a possible anatomic form of Behçet uveitis.85 It may be
Serological testing should be reserved for children with an misdiagnosed as pars planitis. Distinctive features of vitritis in
exposure history or systemic findings suggestive of Lyme Behçet disease include diffuse and severe vitreous haze with an
disease.44,80 acute onset and a spontaneous resolution, recurrent attacks, infer­
Sarcoidosis should be considered in the differential ior pearl‐like precipitates that appear as the vitritis starts to resolve,
diagnosis of childhood pars planitis. Vitritis is typically and the absence of snowballs or snowbanks. Unlike snowballs
bilateral and characterized by the presence of snowballs which present as mobile, round and white vitreous collections,
or string of pearls vitreous opacities81 with or without pearl‐like precipitates are small, immobile, and are located on the
snowbanking.82 Associated findings may include mutton surface of the retina. They tend to accumulate in a linear pattern
fat keratic precipitates, iris nodules, periphlebitis, and mul­ along the edge of the vitreous base, but may also show a scattered
tiple chorioretinal peripheral lesions.81 Young children pattern. They disappear completely in a couple of weeks.86 Optic
with sarcoidosis do not typically have pulmonary involve­ disc hyperfluorescence, CME, and fern-like capillaritis may be
ment, but may present with polyarthritis, skin nodules, and seen on FA in both Behçet uveitis and pars planitis.86
uveitis. Serum ACE levels should be interpreted with cau­ Fuchs uveitis is frequently misdiagnosed as IU and particularly
tion because ACE levels are found to be higher in children pars planitis. In fact, vitritis associated with mild optic disc hyper­
than in adults.83 Familial juvenile systemic granulomatosis, fluorescence and peripheral angiographic vasculitis is a common
known as Blau syndrome, has clinical findings similar to feature in Fuchs uveitis. A high index of suspicion is very impor­
childhood sarcoidosis and is characterized by granuloma­ tant not to miss the diagnosis. Vitritis in eyes with Fuchs uveitis is
tous polyarthritis, skin rash and, uveitis. It may be differ­ characterized by varying grades of vitreous cells and/or haze with
entiated from sarcoidosis by family history and acute onset or without vitreous bands/fibrillary structures but no snowballs or
of uveitis.84 snowbanks.87 A careful clinical examination should look for asso­
MS accounts for 2.3 to 33% of cases of IU,74 but this ciated manifestations including diffusely distributed small, stellate
prevalence is much lower in children. Snowballs and/or KPs, diffuse iris atrophy, heterochromia, the absence of posterior
snowbanks may be found in MS-associated IU. Peripheral synechiae and, the absence of CME on OCT.88
vascular involvement is a characteristic manifestation of both Other causes of IU may be mistaken for pars planitis. These
pars planitis and of MS-associated IU, however it seems to conditions should be considered in the presence of particular
be more common in MS-associated IU.74 In addition to that, ocular or systemic clinical findings in specific epidemiological
pars planitis and MS share genetic risk factors, namely HLA- backgrounds. They mainly include inflammatory bowel dis­
DR2 and its split antigen HLA-DR15. Patients with an initial ease, Whipple’s Disease, cat-scratch disease, HTLV1 infection,
diagnosis of pars planitis without MS are at risk of develop­ TINU syndrome, and post-streptococcal uveitis.37
ing MS in approximately 2 to 4%/year. This risk is higher in
those showing peripheral vascular changes.44,74 It has been
Treatment
reported that key criteria for MS-associated IU included
unilateral or bilateral IU and a diagnosis of MS by the Treatment in pars planitis starts with the exclusion of infec­
McDonald criteria.74 tious and non‑infectious causes which may present with IU.
1922 S. KHOCHTALI ET AL.

The decision to treat a patient with pars planitis has always elevation in pediatric uveitis, 7–8 times higher risk has been
been a controversial issue, especially in cases with minimal reported with periocular CS injections. In Yalcinsoy et al.’s94
inflammation and relatively good visual acuity. The guidelines study including 40 eyes of 26 pediatric uveitis patients who
suggested by Forrester et al.89 recommended a VA level worse underwent a single dose of posterior subtenon TA injection as
than 20/40 for treatment decision in pars planitis. However, an adjuvant treatment, 24 (92.3%) were pars planitis cases. IOP
Foster et al.90 emphasized that treating inflammation early and elevation was observed in 47.5% of the eyes requiring glau­
aggressively, and not using a VA threshold, is more effective coma surgery in 10% and subtenon TA deposit excision in
both in the short and long term. They showed that 20% of 11%, and supporting the fact that IOP elevation is more com­
patients who were allowed to wait until VA reached <20/40 for mon, more severe and develops earlier in children.
treatment, were never able to recover normal vision even when Intravitreal TA injection which has been shown to be effec­
treated. Consistently, our current knowledge and experience tive in treating IU and associated macular edema, is associated
suggest that pars planitis is a severe disease which may cause with high rates of complications including cataract, increased
several ocular complications needing an aggressive intraocular pressure, glaucoma, vitreous hemorrhage, retinal
treatment.44,91 We believe that the presence of macular detachment and endophthalmitis.96 In above mentioned study
edema, vitreous haze leading to a decrease in VA, severe by Kothari et al.,95 intravitreal TA administration has been
infiltration of the pars plana, association of retinal vasculitis found to associate with the highest risk of IOP rise in pediatric
and complications such as band keratopathy, cataract, reti­ uveitis population. In the light of previously published litera­
noschisis and even posterior synechiae in at least one eye are ture and our clinical experience showing that the risk for
indications for treatment irrespective of the level of visual cataract development and IOP rise are more common in
acuity.44 Nevertheless, patients with mild disease and good pediatric population, we agree that this technique should
VA with no associated vitreous haze and complication, can remain an emergency procedure when essential structures
be followed without treatment. such as the macula have to be saved immediately while orga­
A stepladder approach is adopted when treating pars pla­ nizing the systemic treatment.97 Another intravitreal treat­
nitis patients. The order of steps, however, may differ accord­ ment method is the dexamethasone implant (Ozurdex®;
ing to the physician’s experience and patient’s clinical Allergan, Irvine, CA, USA) which has been approved for the
picture.44 A four‑step approach consisted of 1. periocular and treatment of intermediate and posterior uveitis in adults.98 As
oral corticosteroids (CS), 2. cryotherapy or laser photocoagu­ its use is off-label in children, experience with pediatric popu­
lation, 3. pars plana vitrectomy and 4. immunosuppressive lation is limited. Although few studies reported the intravitreal
treatment, described by Kaplan,92 was then modified by dexamethasone implant as an effective and safe therapy for
Foster90 suggesting a five‑step approach. Foster90 has recom­ controlling childhood intraocular inflammation including
mended systemic non‑steroidal anti‑inflammatory drugs IU,99–102 more data are required to establish the need for
(NSAIDs) as a second step in patients not responding to repeated injections and the frequency of ocular complications
three periocular CS injections. In this modified stepladder in the long term. Thus, as with intravitreal TA, dexamethasone
approach, a short-term use of systemic CS which made the implant should be used as a last resort in emergent conditions.
third step was followed by cryotherapy or laser photocoagula­ We have to remember that the risks and benefits of local versus
tion and pars plana vitrectomy (PPV) or immunosuppressive systemic treatment should be weighed carefully for each
treatment as fourth and fifth steps, respectively. patient.
As the experience of ophthalmologists with the use of Patients with bilateral involvement, severe ocular inflam­
immunosuppressive agents and new biological treatments mation in at least one eye, or unilateral disease unresponsive to
has increased, previously proposed treatment algorithms periocular CS injections need to be treated systemically. A dose
have also changed over time. In the current practice, the first of 1–1.5 mg/kg/day of prednisone tapered according to clinical
step of treatment is still the CS which is essential for control­ response is preferred by most of the uveitis specialists. As high-
ling active inflammation. Topical, periocular, systemic, and dose short-term use of systemic CS is safer than chronic low
intravitreal CS may be used depending on the location and dose use, intravenous pulse methylprednisolone therapy (30
severity of intraocular inflammation. Topical CS known to be mg/kg) may be administered when more rapid and potent
ineffective for treatment of IU especially in phakic cases, are action is needed.3 It is very important to remember that CS-
used only when anterior segment inflammation is present. related systemic complications such as growth retardation,
Systemic or periocular CS, however, are required in majority weight gain, and adrenal suppression in the long-term, and
of patients with pars planitis. Periocular CS injections are ocular complications such as cataract and steroid-induced
useful particularly in the presence of macular edema and in glaucoma are more common in children compared to
patients with unilateral or asymmetrical involvement.44 adults.19 Thus, in patients who require long‑term treatment,
Subtenon injection of triamcinolone acetonide (TA) is the steroid‑sparing immunosuppressive agents should be
mostly used periocular injection method. An improvement of the second step of treatment. Because of its long‑term safety
at least two Snellen lines of VA following posterior subtenon profile, easy administration and well tolerance, oral or subcu­
injection of TA has been reported by Helm et al.93 Increased taneous methotrexate (MTX) which is an antimetabolite, is the
intraocular pressure (IOP), development of cataract and apo­ treatment of choice in pediatric population. The recom­
neurotic ptosis are the most common complications of perio­ mended starting dose is 10–15 mg/m2/week orally or subcuta­
cular CS.37,94,95 In a multicenter study conducted by Kothari neously. Weekly use of subcutaneous MTX provides higher
et al.95 and evaluating the risk and risk factors for IOP bioavailability compared to oral use. MTX should be used with
 OCULAR IMMUNOLOGY AND INFLAMMATION 1923

folic acid supplements to prevent side effects.5,44,103 A slow of 23 patients using ADA revealed that the drug was well
onset of action and development of aversion in the long-term tolerated and effective for decreasing uveitis attacks and the
are the major disadvantages of MTX especially in pediatric need for CS in 95%. CS could be stopped in 16/23 (70%) of
population.5 In patients resistant to or not tolerating MTX patients. Besides, switching to ADA was found to be bene­
treatment, mycophenolate mofetil (1–3 g/day), azathioprine ficial in cases with CS-induced IOP rise. Authors suggested
(1–3 mg/kg/day) and cyclosporine (3–5 mg/kg/day) may be a treatment algorithm that includes ADA for the treatment
used alone or in combination. Because these agents need 4‑8 of pars planitis patients.91 Another recent study that evalu­
weeks to become effective, CS should be given concomitantly ated the efficacy and safety of ADA combined with antime­
until the immunosuppressive agent is expected to act.44 Due to tabolite in pediatric patients with pars planitis showed that
their serious potential side effects and the availability of fast- intraocular inflammation could be controlled in all patients
acting biologic agents nowadays, alkylating agents such as resulting in steroid-free remission, decrease in central macu­
cyclophosphamide and chlorambucil should be avoided espe­ lar thickness and increase in VA. Authors stated that ADA is
cially in children. The use of immunosuppressive agents in an effective and safe agent either as a first-line or as a salvage
patients with pars planitis has been shown to positively affect treatment116 (Figure 2). In an international multicenter study
the course of the disease in terms of clinical and visual conducted by Vitale et al.,117 analyzing real-life data of
improvement and reduction of systemic CS dosage without pediatric non-anterior uveitis patients with severe involve­
severe side effects.104 ment and treated with ADA, all 21 patients (36 eyes) bene­
Biologic agents comprise the third step of treatment in fited from ADA administration. Eleven patients (19 eyes) did
patients not responding or intolerant to conventional immu­ not have any new attack and 10 patients (17 eyes) showed
nosuppressive agents. Clinical experience suggests promising a significant clinical improvement with a decrease in severity
efficacy from the use of anti‑TNF‑α agents especially in and/or frequency of inflammatory attacks. Furthermore, the
refractory ocular inflammation. Both infliximab (IFX) and frequency of macular edema and retinal vasculitis and the
adalimumab (ADA) have been shown to be effective in mean daily CS dosage decreased significantly. Patients with
pediatric uveitis including pars planitis.103,105–109 IFX is a full response to ADA treatment were mostly IU/pars pla­
administrated parenterally with a loading dose of 3–5 mg/ nitis and posterior uveitis cases. This result has been attrib­
kg at 0–2–6 weeks, followed by a maintenance dose of 3–10 uted to a higher use of systemic CS and conventional
mg/kg every 4 weeks. Low-dose MTX may be combined to immunosuppressives when starting ADA treatment in
avoid antibody formation. Susceptibility to infections, reacti­ patients with IU/pars planitis.117
vation of TB and infusion reactions are the major concerns.44 In patients who have failed ADA treatment, switching to
ADA is used subcutaneously in a dosage of 20–40 mg every another anti-TNF agent may be considered. In the study by
two weeks following a loading dose of 40–80 mg, depending Ashkenazy et al.118 including 13 pediatric uveitis patients in
on the child’s weight. The standard dosing regimen is 20 mg whom 4 (31%) had pars planitis and all were refractory to
in children weighing <30 kg and 40 mg in children weighing weekly use of ADA and antimetabolite combination, inflam­
≥30 kg. A weekly dosing was found to be effective and safe in mation control could be obtained with IFX in 100%. There is
children who did not respond to the standard dose.110 no evidence however for the use of other anti-TNF agents
Adverse events are similar to IFX, but as a fully-humanized golimumab and certolizumab in pediatric pars planitis.
monoclonal antibody, it has a decreased risk for allergic Because of the association between pars planitis and MS,
reaction and antidrug antibodies development. Studies com­ and the potential of anti‑TNF‑α agents to develop demyelinat­
paring these two anti‑TNF‑α agents in terms of remission of ing disease, it is important to remember that extreme caution
inflammation in pediatric chronic non‑infectious uveitis, is needed when both starting and using these agents.119
showed a similar effect. However, ADA was found to be Current guidelines recommend avoiding anti-TNF-α therapy
more efficient in preventing the uveitis attacks and main­ in patients with a personal history or familial occurrence of MS
taining the remission. Consistently, a recent meta-analysis by or other demyelinating diseases.120–122
Maccora et al.109 evaluated the efficacy of anti-TNF agents in In refractory cases that have failed or had a contra-
pediatric chronic uveitis and results with ADA were reported indication or intolerance with anti-TNF treatment, tocilizu­
to be superior compared to IFX. Moreover, as its efficacy has mab (TCZ) may be considered as an alternative. In a small
been shown in randomized placebo-controlled trials of series of pediatric refractory intermediate and posterior uveitis
chronic anterior uveitis in children,111,112 and in non- cases (5 and 2 cases, respectively), TCZ has been shown to
anterior uveitis in adults,113,114 ADA is the only approved improve macular edema and capillary leakage on FA.123
biologic agent for the treatment of non-infectious uveitis. Its Pars plana vitrectomy (PPV) makes the fourth step of
subcutaneous administration which does not need hospitali­ treatment particularly in patients developing complications
zation is another advantage making it the first choice for such as vitreous condensation, vitreous hemorrhage, retinal
anti-TNF‑α treatment in children. Also, the use of ADA as detachment, epiretinal membranes causing retinal traction and
the first anti‑TNF‑α agent has been reported to be more macular hole. This surgical step may also be an effective treat­
effective as compared to its use in cases of IFX failure.115 ment option in patients with active inflammation and cystoid
In a recent study by Ozdemir and Ozdal,91 including 59 macular edema refractory to medical treatment, providing
patients with pars planitis, of whom 51 (86.5%) were chil­ a mechanical clearance of inflammatory mediators and debris.
dren, ADA has been reported as an effective agent especially Promising results of PPV on the course of pediatric and
in patients refractory to conventional treatment. Evaluation juvenile chronic uveitis, providing a significant improvement
1924 S. KHOCHTALI ET AL.

in VA and reduction in postoperative CME have been <16 years of age at presentation and reported that VA
reported.124–127 improved in patients treated with immunosuppressive
This four-step approach may be modified according to the agents, except those with posterior segment complications
severity of ocular inflammation and patient’s needs. For exam­ and amblyopia at presentation. An adequate preoperative
ple, in patients presenting with severe intraocular inflamma­ control of inflammation, a meticulous surgical technique,
tion and serious ocular complications; immunosuppressive and a good postoperative inflammation control are crucial
and CS combination and/or even an anti-TNF agent may be for successful cataract surgery in uveitis patients in general,
started as the first step and periocular CS injection can be and pars planitis in particular.
performed as an adjuvant, if significant macular edema and/
or vitreous condensation accompany.
Course and prognosis
Cryotherapy and laser photocoagulation were suggested
before the immunosuppressive treatment both in Kaplan’s The natural course of pediatric pars planitis is a prolonged
and Foster’s stepladder approaches.90,92 The rationale for per­ course of vitreous inflammation with remissions and
forming these treatment modalities was to induce regression of exacerbations that can lead to substantial ocular complica­
vitreous base neovascularization and consequently stabilize the tions and visual loss.28,41,136 The insidious onset of the
inflammation. Although favorable results with cryotherapy disease makes early diagnosis and treatment difficult, and
have been previously reported,128–130 cryotherapy may aggra­ most cases are referred after the emergence of complica­
vate blood‑ocular barrier disruption, induce vitreous contrac­ tions. Poor visual outcome in pediatric pars planitis is
tion, and increase the possibility of retinal detachment in attributed to several factors, including younger age at
a predisposed eye.90 Compared to cryotherapy, laser photo­ presentation.6,28 This can be explained by a more severe
coagulation is an easier and safer method with fewer ocular form of the disease in the younger age group. Moreover,
complications. It has been shown to be effective for the treat­ younger children can be either asymptomatic or have diffi­
ment of peripheral retinal neovascularization and suggested to culty articulating their symptoms, leading to a delayed pre­
diminish the inflammation in pars planitis by decreasing the sentation with more severe inflammation and ocular
release of angiogenic factors.131,132 In the current treatment complications.6,28 This highlights the importance of educat­
approach, laser photocoagulation is not considered as ing families about eye health and seeking medical attention
a treatment step alone; but as an adjunctive modality especially for children who describe any visual symptoms. Early
when pars planitis is associated with peripheral ischemia, recognition and prompt initiation of appropriate treatment
neovascularization, retinal traction or retinoschisis.44,91,133 are essential to control the inflammation and prevent visual
A simplified updated treatment algorithm is shown in loss.28,91,116 Other poor prognostic factors that have been
Figure 5. reported are male gender, duration of uveitis of more than
Cataract surgery using phacoemulsification and intraocu­ 3 years, anterior chamber cells, marked vitreous haze with
lar lens implantation has been reported to be safe and suc­ snowballs and snowbanks, optic disc edema, and macular
cessful in pars planitis series including pediatric cases.134 edema.6,44
Albavera-Giles et al.135 performed the cataract surgery on Eyes with more aggressive inflammation are more prone
22 patients with pars planitis, of whom 19 (86.4%) were to develop complications, including CME and retinal

Figure 5. Summary algorithm for the treatment of pars planitis in children.

 OCULAR IMMUNOLOGY AND INFLAMMATION 1925

detachment. Previous studies have shown that CME is the Funding

leading cause of significant visual loss in children with pars
The author(s) reported there is no funding associated with the work
planitis.6,7,33,44,48,61 Kalinina et al.6 found that optic disc featured in this article.
edema and snowbanking are associated with the later devel­
opment of CME. Therefore, those children need close mon­
itoring with an earlier threshold for initiating conventional References
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