Severe recurrent corneal calcification following autologous submandibular gland translocation

1
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

2

• 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.

3

• 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.

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• 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.

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• 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 Bowmans
membrane in contrast to typical band shaped
keratopathy. Hematoxylin and eosin stain (A) and
alizarin red (B).
A B
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Figure 2 Recurrent band keratopathy 2 weeks
after corneal transplantation.
Figure 3. Histopathology of corneal button
showing sharply demarcated calcific deposits
replacing Bowmans layer and penetrating into
superficial stroma in an area of epithelial
defect. Hematoxylin and eosin stain (A) and
alizarin red (B).
A B
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• 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 Bowmans 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 solutions3-4, 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 patients salivary gland
  redirection played a major role in the
  calcification process.

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Table 1. Inorganic chemistry of saliva, tears,
and serum
Submandibular saliva Lacrimal gland tears Serum
Calcium Concentration (mmol/L) 1.7-2.2 (saliva 1.3-1.7) 0.36-0.90 1.1
Phosphate Concentration (mmol/L) 6.0 ( saliva 1.93-8.71) 0.22 1.42
pH 6.4 7.45 (7.14-7.82) 7.40 (7.35-7.45)

• 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.

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• 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
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• 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 Bowmans membrane. This direct access
  to Bowmans 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.

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• 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.

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