Severe recurrent corneal calcification following autologous

Download Report

Transcript Severe recurrent corneal calcification following autologous

Severe recurrent corneal calcification
following autologous submandibular
gland translocation
RM Santaella MD, HT McGee MD, WD Mathers MD
Department of Ophthalmology
Oregon Health & Science University
Portland, OR
Abstract:

Purpose: To report severe recurrent corneal calcification as
an adverse effect following translocation of autologous
submandibular gland and to identify factors that may
contribute to the development of this effect.
 Methods: Case report
 Case: 84 y.o. female with severe dry eye and persistent
epithelial defect underwent autologous submandibular gland
translocation to the right eye. Excellent ocular surface
moisture was achieved, however, the patient developed
severe corneal calcification requiring penetrating
keratoplasty. This calcification then rapidly recurred in the
corneal graft.
 Conclusion: Recurrent and difficult to treat calcific band
keratopathy may result following otherwise successful
autologous submandibular gland transplantation as
treatment for dry eye.
Introduction:

Autologous transplantation of the submandibular salivary
gland has been previously described for treatment of
severe, refractory dry eye1.
 While effective at providing moisture to the ocular surface,
the procedure can lead to irregular tear production and
overflow tearing2.
 Calcific band keratopathy occurs when calcium salts,
primarily in the form of hydroxyapatite, are deposited in the
superficial layers of the cornea.
 This deposition has been described in several systemic as
well as local ocular disorders3.
 To our knowledge, however, this is the first report of severe
recurrent corneal calcification following salivary gland
redirection.
Case:
 An 84 year old caucasian female with severe dry eye and filamentary
keratitis underwent a submandibular gland redirection procedure as an
adjuvant treatment for an epithelial defect in her right eye which had
been persistent for 5 months.
 During her 2 week postoperative visit she was noted to have developed
significant band keratopathy in the area of the persistent epithelial defect
(Figure 1). Moisture from the salivary gland redirection was very good.
 A penetrating keratoplasty was performed to restore a healthy ocular
surface.
 At the 1 week visit a small epithelial defect was noted.
 At 2 weeks, dense calcification was again noted on the transplanted
graft with the area of the epithelial defect being affected most (Figure 2).
 Chelation using EDTA performed 1 month after the corneal
transplantation was unsuccessful.
 A repeat systemic workup (and review of previous labs) for band
keratopathy was unremarkable.
 A second corneal transplant was required 1 month after the first graft
due to corneal melting.
 A total epithelial defect was noted the 1st post operative day, and
recurrent calcification was noted again on the 2nd postoperative day.
Figure 1: Severe band keratopathy noted 2
weeks after submandibular gland
transplantation. The dense inferior
portion corresponds to the area of prior
epithelial defect.
Figure 3. Histopathology of
recipient corneal button showing
calcific deposits beneath
Bowman’s membrane in
contrast to typical band shaped
keratopathy. Hematoxylin and
eosin stain (A) and alizarin red
(B).
A
B
Figure 2: Recurrent band keratopathy 2
weeks after corneal transplantation.
Figure 3. Histopathology of
corneal button showing sharply
demarcated calcific deposits
replacing Bowman’s layer and
penetrating into superficial
stroma in an area of epithelial
defect. Hematoxylin and eosin
stain (A) and alizarin red (B).
A
B
Discussion:
 Band-shaped keratopathy (BSK) has been described in association with
several factors, including systemic disorders usually associated with
calcium phosphate metabolism, uveitis, use of pilocarpine with mercurial
preservatives, viscoelastics, and intraocular silicone oil3-8.
 Calcification in BSK has been described to occur at the level of
Bowman’s membrane (Bowman 1849).
 The calcium in BSK can build in the subepithelial space to the point
where it disrupts the epithelium, but that is usually a late finding.
 Rapid calcium deposition has been described in association with
epithelial defects and corneal grafts in conjunction with the use of topical
eye medications containing phosphates or phosphate buffered solutions34, 9-12.
 The calcification noted in this patient appears to be similar to the more
rapid deposition associated with topical phosphate containing
medications and epithelial compromise.
 This patient had been on preparations of prednisolone acetate and
timolol that both contained phosphates among their inactive ingredients:
EconoPred (Prednisolone acetate 1%) and Timolol 0.5% both
manufactured by Alcon Laboratories, (Fort Worth, TX). However, the
calcification recurred despite discontinuation of these phosphate
containing medications and repeat corneal transplantation.
 We believe that this patient’s salivary gland redirection played a major
role in the calcification process.
Table 1. Inorganic chemistry of saliva, tears, and serum
Lacrimal gland tears
Serum
1.7-2.2
(saliva 1.3-1.7)
0.36-0.90
1.1
6.0
( saliva 1.93-8.71)
0.22
1.42
6.4
7.45 (7.14-7.82)
7.40 (7.35-7.45)
Submandibular saliva
Calcium Concentration (mmol/L)
Phosphate Concentration (mmol/L)
pH
Discussion:
 The difference in pH, calcium and phosphate concetrations are key
features that contributed to the severe calcification seen in this
patient.
 Tears have a lower calcium concentration than saliva or serum13-15
and, while there is no direct association between serum calcium
concentration and tear concentration16, relatively minor
disturbances, such as those seen in renal failure, can result in
significant calcium deposition such as BSK.
 Saliva from the submandibular gland, usually has much higher
concentrations of both calcium and phosphate than are found in
lacrimal gland tear secretions13,17. (see Table 1)
 The pH of saliva and submandibular gland secretions is also lower
than that of the tear film13-15.
Discussion:









Saliva protects teeth from dissolution18.
This is accomplished by bathing teeth in a supersaturated solution with
respect to the minerals which compose teeth13,15.
Hydroxyapatite and other forms of apatite are the major constituents of teeth.
In the cornea, calcium deposition also typically occurs as hydroxyapatite9.
The balance between dissolution and precipitation is governed by the
dissociation equilibrium of hydroxyapatite.
This equilibrium is dependent on the concentrations of ions in solution.
In the case of hydroxyapatite (Ca10(PO4)6(OH)2) these ions are calcium,
phosphate and hydroxide.
However, the dissociation equilibrium of hydroxyapatite is very sensitive to pH.
In the mouth a critical pH of 5.2 has been found in which a pH higher than 5.3
tends to lead to precipitation of tooth enamel and lower than 5.2 leads to tooth
dissolution13.
Figure 4. The dissociation
equilibrium equation for
calcium hydroxyapatite
Discussion:




The association of corneal exposure and the interpalpebral location
of BSK has been well described20. Increased tear evaporation
leading to an increase in tonicity and ion concentration within the
tear film is a factor that also plays a role in the dissociation
equilibrium shifting the equilibrium towards precipitation.
Exposure can also lead to epithelial barrier dysfunction and
breakdown exposing a direct access to Bowman’s membrane. This
direct access to Bowman’s membrane may be a factor in the speed
at which calcification occurs.
Our patient had full eyelid closure and was treated with aggressive
lubrication with ointment and despite the lubrication efforts she
developed severe calcification.
This patient was treated with oral pilocarpine hydrochloride
(Salagen, MGI Pharma) at 5mg PO three times a day throughout the
time course of her corneal calcification. Perhaps this medication
may have also contributed in the development of her condition by
increasing the amount of secretions or perhaps the composition of
the submandibular saliva. However, a study measuring change in
the salivary constituents on patients with graft versus host disease
treated with pilocarpine showed no change in the calcium or
phosphate concentrations21.
Conclusions:
 There are several variables that may contribute
to corneal calcification in the setting of
submandibular gland transplantation as
treatment for severe dry eye, including calcium
and phosphate concentrations, pH, tonicity,
epithelial disruption, and degree of tear
evaporation.
 Dense corneal calcification is a severe and
difficult to manage complication that may arise
after autologous transplantation of the
submandibular salivary gland for dry eye.
References:
1.
Geerling G, Sieg P, Bastian GO, Laqua H. Transplantation of the autologous submandibular gland or most
severe cases of keratoconjunctivitis sicca. Ophthalmology 1998; 105: 327-335.
2.
Leibovitch I, Hoyama E, Limawararut V, Crompton J, Selva D. Novel technique to control hypersecretion from
a transplanted autologous submandibular salivary gland for keratoconjunctivitis sicca. Cornea 2006; 25: 125153.
3.
Smolin G. Dystrophies and degenerations. In: Smolin G, Thoft RA. The Cornea. 2nd ed. Boston, Mass:Litle
Brown & Co. 1989:429.
4.
Kennedy RE, Primitive RD, Landers PM. Atypical band keratopathy in glaucomatous patients. Am J
Ophthalmol. 1971;72:917-922
5.
Coffman MR, Mann PM. Conreal subepithelial deposits after use of sodium chondroitin. Am J Ophthalmol.
1986;102:276.
6.
Nevyas AS, Raber IM, et al. Acute band keratopathy following intracameral Viscoat. Arch Ophthalmol.
1987;105:958.
7.
Binder PS, Deg JK, kohl FS. Calcific band keratopathy after intraocular chondroitin sulfate. Arch Ophthalmol.
1985;105:1243.
8.
Sternberg P Jr., Hatchell DL, et al. The effect of silicone oil on the cornea. Arch Ophthalmol. 1985;103:90.
9.
Taravella MJ, Shulting RD, MAder TH, et al. Calcific band keratopathy associated witht the use of topical
steroid-phosphate preparations. Arch Ophthalmol. 1994;112:608-613.
10.
Bernauer W, Thiel MA, et al. Corneal calcification following intensified treatment with sodium hyaluronate
articial tears. Br J Ophthalmol. 2006;90:285-8.
11.
Daly M, Tift SJ, Munro PM. Acute corneal calcification following chemical injury. Cornea 2005; 24:761-765.
12.
Schlötzer-Schrehardt U, Zagorski Z, Holbach LM, et al. Corneal stroma calcification after topical steroidphosphate therapy. Arch Ophthalmol 1999; 117:1414-1418.
13.
Larsen MJ, Pearce EIF. Saturation of human saliva with respect to calcium salts. Arch Oral Biol 2003; 48:317322.
14.
Van Haeringen NJ. Clinical biochemistry of tears. Surv Ophthalmol. 1981; 26:84-96.
15.
Cummings CW, Haughey BH, Thomas JR, Harker LA, Flint PW. Composition of saliva. In: Cummings:
Otolaryngology: Head & Neck surgery, fourth edition. Mosby, Inc. 2005.
16.
Avisar R, Savir H, Sidi Y, Pinkhas J. Tear calcium and magnesium levels of normal subjects and patients with
hypocalcemia or hypercalcemia. Invest Ophthalmol. 1977; 16: 1150-1151
17.
Tsubota K, Higuchi A. Serum application for the treatment of ocular surface disorders. Int Ophthalmol Clin.
2000; 40:113-122. Review.
18.
Zero DT, Lussi A. Erosion-- Chemical and biological factors of importance to the dental practitioner. Int Dent J
2005; 55:285-290.
19.
Fosdick LS, Starke C, Jr. Solubility of tooth enamel and saliva at various pH levels. J Dent Res 1939; 18:417430.
20.
O’Connor GR. Calcific band keratopathy. Trans Am Ophthalmol Soc. 1972; 70:58-85.
21.
Nagler R. The effect of pilocarpine on salivary constituents in patients with chronic graft versus host disease.
Arch Oral Biol 2001; 46:689-695.