On the Ocular Findings in Ochronosis
On the Ocular Findings in Ochronosis
Our literature search revealed 74 articles. Within them we found 36 relevant case reports including 40 patients published between 1942 and 2012. Excluded articles and respective reasons are given in Table 1. The mean age of our patients was 61.0 (Standard deviation: ±9.5) years, with the youngest patient being 14 and the oldest 83 years old. The age at which the ocular findings first appeared was only given in eight articles and was 40.6 (Standard deviation: ±9.8, range 25 to 54) years.
The most common finding was hyperpigmentation of the sclera which was present in 33 patients. This scleral pigmentation was mostly observed symmetrically to both sides of the cornea within the palpebral fissure having blurred margins (Figure 2, left, with permission). In most reports it remains unspecified at which level of the sclera the pigmentations were seen. D'Alessandro et al. see them in the deeper layers of the sclera. Conjunctival changes were also frequent (22 cases) but more heterogeneous in appearance. There are four main types of appearance which may also occur in combination: 1) Small "vermiform" or "tube-like" pigment deposits (Figure 2, middle, with permission), 2) brown pingecula-like, 3) dot like or 4) laminar structures. Dilatated conjunctival vessels can be present and seemingly supply the pigmented areas. Findings on the ocular surface are usually symptomless. "Sicca"-symptoms or foreign body sensation have only been reported twice in literature.
(Enlarge Image)
Figure 2.
Biomicroscopic findings in ochronotic eyes. Left: Symmetric brown scleral pigmentation at 3 and 9 o'clock (w. permission [31]). Middle: "Vermiform" pigment accumulation in the conjunctiva (Courtesy of Dr. U. Hackethal [88]). Right: "Oil drops" of the corneal limbus (w. permission [31]). All images show the right eye.
Pigment may also accumulate in the opaque portion of the limbus where it forms "oil drop"-like brown spots (Figure 2, right, with permission), seen in 30 cases. In analog to the pigmentations of sclera and conjunctiva, also the limbal pigment drops follow a horizontal orientation. They are located at the level of the Bowman's Membrane or slightly inferior to it. In one case they were explicitly noted as the first feature of ochronosis in a 25 years old patient.
Severe progressive astigmatism has been reported twice. It was attributed by the authors to ochronotic accretions that were integrated from the sclera into the limbus and may have lead to corneoscleral thinning. Both patients were in their 70ies when astigmatism began to develop and in both cases the axis of the cylinder was around 0° thus oriented in a right angle to the pigment. Astigmatism progressed by 6 dpt within two years in one case and by 7 dpt within 11 years in the other. Ehongo et al. attempted a corneal transplant and bilateral thread placement. Both attempts did not bring enduring success, however re-progression was much slower after thread placement.
Hyperpigmentation of the chamber angles has been reported four times. Several other findings have only been observed sporadically. They include brown pigmentation of the optic disc, the retina and the vitreous. In addition, pigment inclusions may occur at the iris or fit to the posterior surface of the lens.Table 2 summarizes the most common ophthalmologic findings.
Pigment in the chamber angles might lead to increased intraocular pressure (IOP) and thereby to glaucomatous lesions. In total, 15 articles commented on the IOP, eight reporting values above 21 mmHg. Interestingly, in three of them the patients suffered from acute secondary glaucoma, always attributed to central vein occlusion. Among the remaining cases, a primary glaucoma was only described in one case while an increased intraocular pressure was documented, but not further discussed in two. Noteworthy, gonioscopy is only described in two of the cases indicating elevated IOP. It revealed a hyperpigmented chamber angle each time.
There are two reports of acute recurrent anterior uveitis and ochronosis. In the first one uveitis is claimed to be the initial manifestation of ochronosis. In the second one the patient has had uveitis in history and the authors see no association with ochronosis. Both patients suffered from unilateral uveitis. While it was described as side-alternating and non-granulomatous in first case, in the other case recurrent episodes of specific uveitis on always the same – now blind – eye were reported.
We found six detailed histopathologic descriptions of the whole bulbus and four descriptions of ocular biopsies. Ochronotic pigment is usually referred to as melanin-like which is true for the non-tinged tissue where it has a brown to olive, non-birefringent appearance. Histochemically, it rather behaves like elastin as being positively stained by van Gieson or Movat-pentachrome but not by Fontana. In hematoxilin-eosin it is seen as light wine-red to eosinophilic but still with a pale olive appearance (Figure 3, with permission).
(Enlarge Image)
Figure 3.
Histopahtologic slice through a specimen obtained from the conjunctiva (Hematoxilin-Eosin staining). P: Ochronotic pigment, E: Conjunctival epithelium, SP: Substantia propria, G: conjunctival vessel. Courtesy of Dr. U. Hackethal [88].
In accordance to the clinical findings, also histologically the central cornea is usually clear. Though phagocytised pigment may well occur inside central endothelial cells. The limbal "oil-drops" are correlated by globular accretions adjoining the Bowman's membrane or infiltrating the anterior stroma. Kampik et al. describe them as rather small granules that are located around or even inside the keratocytes.
All parts of the sclera can be affected by ochronotic pigment granules. However, the major part of the ochronotic pigment is found to reach from the insertion of the rectus muscles towards pars-plana. Pigment can be either extracellular, forming beads along collagene fibers, or intracellular in macrophages and fibrocytes. Areas of strongest pigment accumulation were associated with degeneration of sclera fibers. Inflammatory reactions were not seen in any of the histopathologic works assessed here. Their absence is explicitly mentioned in two works.
The structures of chamber water production and drainage are usually not commented on. However, Allen et al. describe deposit of pigment dust in the ciliar process and ciliar body. The only statements on chamber angles are made by Stürmer et al. and Rones et al. who describe them as open but do not state if pigmented or not.
In the cases analyzed here, the initial diagnosis was often not determined correctly. In four cases, the initial diagnosis was melanoma. In another case, a patient was diagnosed as anklyosating spondylitis and referred to the ophthalmologist to exclude an accompanying iridocylitis. Finally, in a case where conjunctival "vermiform" findings were the leading sign, parasitosis had been suspected.
Results
Our literature search revealed 74 articles. Within them we found 36 relevant case reports including 40 patients published between 1942 and 2012. Excluded articles and respective reasons are given in Table 1. The mean age of our patients was 61.0 (Standard deviation: ±9.5) years, with the youngest patient being 14 and the oldest 83 years old. The age at which the ocular findings first appeared was only given in eight articles and was 40.6 (Standard deviation: ±9.8, range 25 to 54) years.
Clinical Findings
The most common finding was hyperpigmentation of the sclera which was present in 33 patients. This scleral pigmentation was mostly observed symmetrically to both sides of the cornea within the palpebral fissure having blurred margins (Figure 2, left, with permission). In most reports it remains unspecified at which level of the sclera the pigmentations were seen. D'Alessandro et al. see them in the deeper layers of the sclera. Conjunctival changes were also frequent (22 cases) but more heterogeneous in appearance. There are four main types of appearance which may also occur in combination: 1) Small "vermiform" or "tube-like" pigment deposits (Figure 2, middle, with permission), 2) brown pingecula-like, 3) dot like or 4) laminar structures. Dilatated conjunctival vessels can be present and seemingly supply the pigmented areas. Findings on the ocular surface are usually symptomless. "Sicca"-symptoms or foreign body sensation have only been reported twice in literature.
(Enlarge Image)
Figure 2.
Biomicroscopic findings in ochronotic eyes. Left: Symmetric brown scleral pigmentation at 3 and 9 o'clock (w. permission [31]). Middle: "Vermiform" pigment accumulation in the conjunctiva (Courtesy of Dr. U. Hackethal [88]). Right: "Oil drops" of the corneal limbus (w. permission [31]). All images show the right eye.
Pigment may also accumulate in the opaque portion of the limbus where it forms "oil drop"-like brown spots (Figure 2, right, with permission), seen in 30 cases. In analog to the pigmentations of sclera and conjunctiva, also the limbal pigment drops follow a horizontal orientation. They are located at the level of the Bowman's Membrane or slightly inferior to it. In one case they were explicitly noted as the first feature of ochronosis in a 25 years old patient.
Severe progressive astigmatism has been reported twice. It was attributed by the authors to ochronotic accretions that were integrated from the sclera into the limbus and may have lead to corneoscleral thinning. Both patients were in their 70ies when astigmatism began to develop and in both cases the axis of the cylinder was around 0° thus oriented in a right angle to the pigment. Astigmatism progressed by 6 dpt within two years in one case and by 7 dpt within 11 years in the other. Ehongo et al. attempted a corneal transplant and bilateral thread placement. Both attempts did not bring enduring success, however re-progression was much slower after thread placement.
Hyperpigmentation of the chamber angles has been reported four times. Several other findings have only been observed sporadically. They include brown pigmentation of the optic disc, the retina and the vitreous. In addition, pigment inclusions may occur at the iris or fit to the posterior surface of the lens.Table 2 summarizes the most common ophthalmologic findings.
Pigment in the chamber angles might lead to increased intraocular pressure (IOP) and thereby to glaucomatous lesions. In total, 15 articles commented on the IOP, eight reporting values above 21 mmHg. Interestingly, in three of them the patients suffered from acute secondary glaucoma, always attributed to central vein occlusion. Among the remaining cases, a primary glaucoma was only described in one case while an increased intraocular pressure was documented, but not further discussed in two. Noteworthy, gonioscopy is only described in two of the cases indicating elevated IOP. It revealed a hyperpigmented chamber angle each time.
There are two reports of acute recurrent anterior uveitis and ochronosis. In the first one uveitis is claimed to be the initial manifestation of ochronosis. In the second one the patient has had uveitis in history and the authors see no association with ochronosis. Both patients suffered from unilateral uveitis. While it was described as side-alternating and non-granulomatous in first case, in the other case recurrent episodes of specific uveitis on always the same – now blind – eye were reported.
Histopathology
We found six detailed histopathologic descriptions of the whole bulbus and four descriptions of ocular biopsies. Ochronotic pigment is usually referred to as melanin-like which is true for the non-tinged tissue where it has a brown to olive, non-birefringent appearance. Histochemically, it rather behaves like elastin as being positively stained by van Gieson or Movat-pentachrome but not by Fontana. In hematoxilin-eosin it is seen as light wine-red to eosinophilic but still with a pale olive appearance (Figure 3, with permission).
(Enlarge Image)
Figure 3.
Histopahtologic slice through a specimen obtained from the conjunctiva (Hematoxilin-Eosin staining). P: Ochronotic pigment, E: Conjunctival epithelium, SP: Substantia propria, G: conjunctival vessel. Courtesy of Dr. U. Hackethal [88].
In accordance to the clinical findings, also histologically the central cornea is usually clear. Though phagocytised pigment may well occur inside central endothelial cells. The limbal "oil-drops" are correlated by globular accretions adjoining the Bowman's membrane or infiltrating the anterior stroma. Kampik et al. describe them as rather small granules that are located around or even inside the keratocytes.
All parts of the sclera can be affected by ochronotic pigment granules. However, the major part of the ochronotic pigment is found to reach from the insertion of the rectus muscles towards pars-plana. Pigment can be either extracellular, forming beads along collagene fibers, or intracellular in macrophages and fibrocytes. Areas of strongest pigment accumulation were associated with degeneration of sclera fibers. Inflammatory reactions were not seen in any of the histopathologic works assessed here. Their absence is explicitly mentioned in two works.
The structures of chamber water production and drainage are usually not commented on. However, Allen et al. describe deposit of pigment dust in the ciliar process and ciliar body. The only statements on chamber angles are made by Stürmer et al. and Rones et al. who describe them as open but do not state if pigmented or not.
Initial Diagnosis
In the cases analyzed here, the initial diagnosis was often not determined correctly. In four cases, the initial diagnosis was melanoma. In another case, a patient was diagnosed as anklyosating spondylitis and referred to the ophthalmologist to exclude an accompanying iridocylitis. Finally, in a case where conjunctival "vermiform" findings were the leading sign, parasitosis had been suspected.
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