1.

Clinical background
Key symptoms and signs
Phthisis bulbi represents an ocular end-stage disease of various causes and
is defined by atrophy, shrinkage, and disorganization of the eyeball and intraocular
contents (Box 54.1).[1,2] Subjective complaints depend on the etiology and severity
of phthisis bulbi. Typical clinical symptoms and signs include chronic ocular
hypotension (5 mmHg), a shrunken globe, pseudoenophthalmos, intraocular tissue
fibrosis and scarring, vision loss, and recurrent episodes of intraocular irritation and
pain.[3]
Definitionphthisis bulbi
Phthisis bulbi represents an ocular end-stage disease characterized by:
Atrophy
Shrinkage
Disorganization of the eyeball and its intraocular contents
2. Historical development
The term phthisis bulbi derives from the Greek word phthiein or phthinein, meaning
shrinkage or consuming, and was first used by Galen.[3] Over the last 200 years, the
clinical interpretation of phthisis bulbi has often been modified according to the
underlying disease and structural changes; a clear distinction from ocular atrophy
was often difficult and controversial.[4] Hogan and Zimmerman[1] were the first ones
who stated that both terms atrophy and phthisis bulbi refer to consecutive stages
in the degeneration process of a severely damaged eye. Their descriptive
classification system including three different stages (1) ocular atrophy without
shrinkage; (2) with shrinkage; and (3) with shrinkage and disorganization has been
further modified by Yanoff and Fine[2] (Table 54.1).
3. Epidemiology
Epidemiological data on phthisis bulbi are mainly based on retrospective
clinicopathological studies on enucleated eyes.[510] Enucleations are usually the
result of failed ocular treatment or end-stage diseases (i.e., phthisis bulbi) associated
with blind, painful, or cosmetically unacceptable eyes. The incidence of enucleation
in general has slightly decreased during the last decades because of improved
diagnostic and therapeutic approaches, and the trend towards globe-preserving
procedures; however, information on the incidence of phthisis bulbi is limited.[10,11]
In contrast, the prevalence of phthisis bulbi in enucleated eyes is well documented,
ranging from 11.2% to 18.7% with an average of 13.7%, and has remained fairly
stable over the last 60 years (Table 54.2).[59] However, statistical evaluations
indicate a slight increase in the number of enucleations for phthisis bulbi during the
last two decades
4. Genetics
A possible relationship between myotonic dystrophy and ocular hypotony has
been described by Kuechle and co-workers.[14] The examined eyes displayed a
diminished bloodaqueous barrier (BAB) function and diffuse choroidal edema,
presumably due to elevated follicle-stimulating hormone and luteal hormone serum
levels.
5. Diagnostic workup
Phthisical eyes are usually easily accessible for slit-lamp examination, which
allows evaluation of the periocular region and structures of the anterior segment. In
less advanced stages of the disease with a lack of significant corneal opacification,
intraocular fibrosis (i.e., cyclitic membranes) or cataractous changes of crystalline
lens, gonioscopy, direct and indirect ophthalmoscopy, fluorescein angiography, and
optical coherence tomography may be useful for evaluation of the anterior-chamber
angle, choroid, and retina.[15] Once optical visualization of the intraocular structures
is obscured, ultrasound biomicroscopy and other noninvasive diagnostic imaging
techniques such as computed tomography (CT) and magnetic resonance imaging
(MRI) may be applied to validate morphologic abnormalities of the anterior chamber
and ciliary body as well as to exclude intraocular ossification, or possibly foreign
bodies (Box 54.2).[16,17]However, the differential diagnostic utility of
6. Differential diagnosis
Although the underlying diseases and the clinical course of phthisis bulbi are quite
variable, the end-stage disease is rarely missed because of characteristic clinical
features (i.e., small, soft, atrophic eyes), which are often associated with decreased
or lost vision. However, clinicians should be aware of any potential disease entity
which, if not treated properly, may result in a blind, often painful phthisical eye.
Intraocular malignancies (i.e., retinoblastoma, malignant uveal melanoma) should be
taken into consideration if the ocular history is limited and an obvious cause for
phthisis is missing.[6] In addition, congenital abnormalities like microphthalmos and
microcornea should be kept in the differential diagnosis of phthisis bulbi.
7. Treatment
Therapeutic approaches are very limited in phthisical eyes; symptomatic treatment
(i.e., artificial tears, ointments, topical corticosteroids, nonsteroidal eye drops, anti-
infectious agents) may be recommended in patients with mild ocular symptoms (i.e.,
irritation, pain). Contact lenses or scleral shells can be used for cosmetic purposes.
Once phthisical eyes become chronically irritated and painful, enucleation or
evisceration with implantation of an intraocular or orbital implant should be
performed, especially with regard to potential long-term complications (i.e.,
sympathetic ophthalmia, ulceration, perforation) and to exclude intraocular
malignancies.[19,20]
8. Prognosis and complications
The diagnosis of phthisical eyes implies a frustrating clinical situation demonstrating
the result of failed previous ocular therapy in which restoration of the morphologic
and functional integrity of the eye is not possible. Most phthisical eyes eventually
become blind, painful, and cosmetically unacceptable for the patient. Potential
harmful complications include corneal ulceration and perforation with the risk of
ocular and periocular inflammation (i.e., panophthalmitis), sympathetic ophthalmia,
and malignant transformation
9. Pathology

Clinical and pathologic findings of phthisical eyes are variable and depend on the
underlying disease and time interval between primary lesion and enucleation. The
following section describes the main clinicopathological ocular features commonly
seen phthisis bulbi
10. Clinical features
Phthisical eyes are usually easy to detect by inspection of the patient's face and are
summarized in Table 54.3. The diagnosis is simplified due to the unilaterality of the
disease with asymmetry of the eyeballs and interpalpebral fissures. Additional
indirect clinical signs include narrow lid fissures (pseudoptosis), lagophthalmos,
pseudoenophthalmos, small-sized and soft, hypotonic (IOP 5 mmHg) eyes (Figure
54.1A; Box 54.3). Axial displacement in relation to the surrounding structures may
occur in advanced stages, which are often associated with vision loss. The
conjunctiva may be swollen (chemotic) and hyperemic. The appearance of cornea is
variable displaying corneal haze, scarred, vascularization, and dystrophic
calcification (Figure 54.1B). The anterior chamber is usually shallow, demonstrating
a narrow to closed chamber angle. Synechia (peripheral, posterior),
neovascularization of the iris surface and chamber angle (rubeosis iridis), fibrotic or
fibrovascular
11. Macroscopic and microscopic features
A. Gross pathology of the external eye
External examination of enucleated phthisical eyes typically shows a soft and
partially collapsed globe. The shape and size of the eyes may vary depending on the
nature and duration of the underlying disease as well as the age of the patient at the
initial event. Phthisical eyes usually demonstrate a squared-off shape with scleral
buckling behind the insertion line of the horizontal and vertical extrinsic rectus
muscles. Other specimens seem to maintain their normal spherical shape despite
marked shrinkage and decreased volume. On average, phthisical eyes are about
20% smaller in dimension compared to normal-sized adult eyes (24 24
24 mm).
[3]
The cornea is usually flattened, smaller in diameter (20%), and hazy due
to edema, scarring, or dystrophic calcification.
[3]

B. Gross pathology of the internal eye
The cornea and sclera are usually markedly thickened, on average by 80% (cornea)
to 50% (sclera) (Figure 54.2).
[3]
The anterior chamber is often shallow or collapsed;
iris defects (partial, complete) from previous trauma or surgery may be present. The
lens is usually thickened and cataractous. The ciliary body and retina are often
detached and displayed anteriorly by a retrolenticular or epiretinal fibrotic tissue; the
optic nerve head may be pulled into the vitreous cavity. Intraocular hemorrhages
may be present in the anterior chamber, vitreous, or choroid.
12. Histopathology
All intraocular structures may be involved in phthisical eyes (Table 54.3). The cornea
is usually thickened, edematous, scarred, and vascularized (57%); a fibrovascular
tissue and areas of dystrophic calcification may be present in the anterior stroma
next to the epithelium.[3] The posterior stroma and Descemet membrane are thrown
into folds by a fibrous tissue proliferation at the inner surface of Descemet
membrane (stromal downgrowth) (Figure 54.3A). The endothelium, if present, may
display cystic changes of its cytoplasm. Additional pathologic findings of the anterior
chamber may include epithelialization and vascularization of the chamber angle and
iris surface (24%), peripheral and posterior synechia with secondary angle closure,
and fibrous or fibrovascular cyclitic membranes at the pupillary margin (Figure
54.3A).[3] The lens usually displays epithelial proliferation, differential staining of
nucleus and cortex, and clefting of the lens fibrils. Occasionally,

13. Etiology
Phthisis bulbi cannot be understood as a specific clinical entity; rather, it is
considered the endpoint of a number of ocular diseases with various stimuli.
Potential risk factors contributing to phthisis bulbi include failed surgical procedures
(i.e., cataract, glaucoma, retina surgery), infections and inflammation (i.e., keratitis,
uveitis, endophthalmitis), intraocular malignancies (i.e., choroidal melanoma,
retinoblastoma) as well as systemic cardiovascular diseases (i.e., diabetes,
hypertension) (Table 54.1).[3,19,28,29] Although it is not known how long an
individual eye will tolerate a specific ocular damage, virtually all diseased eyes will
finally become atrophic if therapeutic treatment fails.
14. Pathophysiology

A. Aqueous humor dynamics and bloodocular barrier functions
The aqueous humor that fills the anterior and posterior chambers is important
in the physiology of the mammalian eye. It provides oxygen and nutrients for the
avascular tissues of the anterior segment such as cornea, trabecular meshwork, and
lens and subsequently removes metabolic waste products. In addition, it maintains
an IOP of about 15 mmHg that is required for the functional and morphological
integrity of the eye. The aqueous humor is derived from the blood plasma and
secreted in an energy-consuming process (approximately 23 l/min) by a
monolayer of nonpigmented epithelial cells at the inner surface of the ciliary body.
Compared to the plasma, the aqueous has a low protein level (about 0.02 g/ml
compared to 7 g/ml), mainly composed of albumin and transferrin.[30]Other
components include various growth and neurotrophic factors such as transforming
growth factor- (TGF-), acidic and basic fibroblastic growth
B. Ocular hypotony and phthisis bulbi
Ocular hypotony, a key feature of phthisical eyes, is defined as IOP of 5
mmHg at consecutive measurements in an individual eye.[28] While clinical signs
and symptoms are usually reversible in acute and transient stages, chronically
decreased IOP can have deleterious effects on intraocular tissue morphology and
function, eventually leading to phthisis bulbi (Table 54.2).[28,33,34] Although the
underlying pathologies and mechanisms of ocular hypotony may be quite variable,
they all work together, inducing an imbalance of aqueous production and outflow
(trabecular, uveoscleral) (Figure 54.4).[21,28,35,36]Subsequent alterations of
aqueous flow dynamics associated with compromised oxygen supply, nutrition, and
metabolic exchange within the anterior chamber are main points of concern. In
particular, intraocular hypoxia has been shown to contribute to BAB breakdown
associated with invasion of serum components (i.e., proteins, growth factors),
inflammatory cells,
C. Ocular wound healing in phthisis bulbi
Fibrovascular and fibrous tissue proliferation can also be observed after
trauma (i.e., concussion, perforation) or complicated vitreoretinal surgery. Similar to
proliferative vitreoretinopathy (PVR), it represents a specific ocular wound-healing
response, which, if not treated properly, contributes to ocular hypotony and
subsequent atrophy of the globe (Figure 54.4).[25,4244] Potent predisposing risk
factors include long-standing retinal detachment and retinal breaks with release of
RPE cells into the vitreous. Briefly, ocular injury results in breakdown of the blood
ocular barrier with release of serum components and chemotactic factors such as
fibronectin (FN), TGF-, and platelet-derived growth factor (PDGF) into the anterior
chamber and vitreous cavity. These factors accelerate migration, proliferation, and
transformation of inflammatory cells and RPE.[31]Later cells are able to secrete
additional growth factors and cytokines like interleukins

D. Dystrophic calcification and heterotopic ossification in phthisis bulbi
Calcification and ossification are frequent end-stage changes of degenerating
tissues. Both can be observed in phthisical eyes, often associated with chronic
inflammation, multiple traumas, long-standing retinal detachment, or
PVR.[23,24,48,49] Intraocular calcium deposits are mainly composed of calcium
phosphate and carbonate and typically occur in the cornea (band keratopathy), lens,
RPE (drusen), and retina, depending on low carbon dioxide tension due to
metabolic inactivity.[50] In contrast, bone formation usually involves the choroid and
fibrovascular or fibrocellular cyclitic membranes external to the neurosensory retina.
The time between original insult and bone formation is quite variable, ranging from a
few months to several years, with an average of approximately 20
years.[23,48]While trauma seems to be more common in young patients with
formation of compact bone tissue, inflammation is often associated with an
15. Conclusion
Phthisis bulbi represents an ocular end-stage disease that results from wound
healing secondary to various causes such as severe trauma, inflammation,
necrotizing tumors, and/or vascular diseases. It results in vision loss and continues
to be an important cause of blindness. The clinical diagnosis of phthisis bulbi, which
is characterized by atrophy, shrinkage, and disorganization of the globe, is a
frustrating situation since therapeutic approaches are limited to symptomatic or
cosmetic treatment options. Prophylactic procedures and close follow-up visits are
required in patients at high risk for the development of phthisis bulbi.