Secondary Glaucoma in Patients With Familial Amyloidotic Polyneuropathy

Objective  To elucidate the clinical features and surgical outcomes of the treatment of secondary glaucoma associated with transthyretin (TTR)-related familial amyloidotic polyneuropathy (FAP).

Design  Retrospective case study.

Participants  Forty-nine Japanese patients with FAP.

Methods  For all patients, measurement of best-corrected visual acuity, intraocular pressure, and visual fields as well as slitlamp and ocular fundus examinations were conducted and compared. In addition, the exact mutation of the amyloidogenic TTR variants was analyzed for all 49 patients with FAP. The TTR mutations included amyloidogenic TTR (ATTR) Val30Met in 41 patients, ATTR Tyr114Cys in 6, ATTR Ser50Ile in 1, and a compound heterozygous mutation of ATTR Val30Met+ Arg104His in 1.

Results  The onset of secondary glaucoma was defined as elevation of intraocular pressure and glaucomatous changes in visual field defects. Secondary glaucoma was detected in 12 (24%) of the 49 patients. The incidence of secondary glaucoma in patients with the Val30Met mutation (17%) was lower than for the other FAP genotypes (P = .02 using the χ² test). Of 20 glaucomatous eyes, amyloid deposition on the pupil and anterior surface of the lens was found in 18 eyes. Amyloid deposition was found prior to glaucoma in 11 eyes and at the first visit to our clinic in another 7 eyes. In the 11 eyes in which the onset of glaucoma occurred following amyloid deposition along the pupil, the mean ± SD period between the onsets of pupillary amyloid deposition and glaucoma was 2.55 ± 1.43 years (range, 0.2-4.0 years). Further statistical analyses revealed significant relationships between the onset of secondary glaucoma and both amyloid deposition (P<.001) and vitreous opacity (P<.001). Surgical treatment was required in 15 (75%) of the 20 glaucomatous eyes. In 9 (81%) of the 11 eyes that underwent trabeculectomy, the intraocular pressure was well controlled at or lower than 20 mmHg during the follow-up period. In the eyes that underwent combined trabeculotomy and sinusotomy (2 eyes), nonpenetrating trabeculectomy (1 eye), or a cyclodestructive procedure (1 eye), the intraocular pressure was poorly controlled.

Conclusions  Glaucoma is not a rare condition in patients with FAP, especially because liver transplantation now enables patients with FAP to live longer. Careful observation of amyloid deposition along the pupil allows the prediction of glaucoma onset.

TRANSTHYRETIN (TTR)-related familial amyloidotic polyneuropathy (FAP) is an autosomal-dominant disease caused by the deposition of polymerized mutated TTR in the peripheral nerves, gastrointestinal tract, heart, ocular tissues, and other organs.¹ Although amyloidogenic TTR (ATTR)Val30Met is the most common genotype for FAP, more than 80 distinct variants of ATTR have been found in recent molecular biological studies. So far, various mutations of TTR have been found in Japanese patients. Val30Met^2,3 (point mutation at codon 30 from GTG [valine] to ATG [methionine]), Tyr114Cys⁴ (point mutation at codon 114 from TAC [tyrocine] to GTC [cysteine]), and Ser50Ile⁵ (point mutation at codon 50 from AGT [serine] to ATT [isoleucine]) have been identified in our district. The most common form of ATTR variant in Japan, as in the world, is Val30Met.⁶

Vision-threatening conditions within the known ocular complications in patients with FAP include the occurrence of glaucoma and vitreous opacity.^7-10 Although the onset of secondary glaucoma is a well-known complication in patients with FAP, knowledge of the clinical course and prognosis of this condition is far from satisfactory.^8,11,12 Recent developments in liver transplantation have led to the elongation of life expectancies in patients with FAP, which may also influence the significance and clinical course of ocular complications. In addition, although recently developed molecular biological techniques can identify exact mutations in the TTR gene and proteins in patients with FAP, ^13,14 the relationship between the clinical features of ocular complications and the different TTR mutations has not previously been determined.

We examined the incidence and clinical features of secondary glaucoma associated with FAP in Japanese patients (Val30Met, Tyr114Cys, Ser50Ile, and a compound heterozygote of ATTR Val30Met + Arg104His).¹⁵ATTR Val30Met + Arg104His is a double mutation newly found in Japan, one at codon 30 from GTG (valine) to ATG (methionine) and the other at codon 104 from CGC (arginine) to CAC(histidine).

We retrospectively examined the clinical records of 49 Japanese patients(20 men and 29 women) with FAP diagnosed and treated from 1987 to 2002. The mean ± SD age of the patients at the first visit to our clinic was 38.6 ± 11.6 years (range, 25-76 years). All patients were referred to the Departments of Internal Medicine, Neurology, and Ophthalmology at Kumamoto University Hospital, Kumamoto, Japan. In all patients, measurement of best-corrected visual acuity, intraocular pressure, and visual fields as well as slitlamp and ocular fundus examinations were conducted at our ophthalmology department. After obtaining informed consent from the patients, surgical treatment and associated examinations were conducted.

For all 49 patients, molecular biological studies were conducted to identify the exact mutation of the amyloidogenic TTR variants.³ The identified mutations included Val30Met in 41 patients(84%), Tyr114Cys in 6 (13%), Ser50Ile in 1 (2%), and a compound heterozygote of ATTR Val30Met + Arg104His in 1 (2%). At the onset of systemic abnormalities (polyneuropathy), the mean ± SD age was 38.8± 10.7 years (range, 23-73 years) for the 49 patients with FAP. According to the genetic mutation of the TTR variant, the mean± SD age at the onset of polyneuropathy was 38.4 ± 11.1 years(range, 23-73 years) in the 41 patients with Val30Met, 37.0 ± 5.2 years(range, 31-43 years) in the 6 patients with Tyr114Cys, 50 years in the 1 patient with Ser50Ile, and 54 years in the 1 patient with a compound heterozygote of ATTR Val30Met + Arg104His (Table 1).

All patients in this series underwent slitlamp and biomicroscopic examinations to determine the presence of abnormal conjunctival vessels, as in a previous study.¹⁴ The diagnosis of keratoconjunctivitis sicca was made based on the results of the Schirmer test (<5 mm) and fluorescein(and/or rose bengal) staining. The presence of amyloid deposition on the pupil border or on the anterior surface of the lens (Figure 1, A and B) and fringed pupil (Figure 1, C) was also determined. The onset and progression of glaucoma were defined as an elevation in the intraocular pressure (>20 mmHg) as measured by an applanation tonometer, changes in the optic nerve head appearance, and glaucomatous changes in the visual fields.

Trabeculectomy was performed according to the method described by Cairns.¹⁶ The conjunctiva was incised in a limbal-based manner. In 10 glaucomatous eyes, mitomycin C (MMC) at 0.4 mg/mL for 3 to 5 minutes was used intraoperatively. Combined trabeculotomy and sinusotomy was performed as described previously¹⁷ and is a modification of the procedure by Harms and Dannheim.^18,19 Nonpenetrating trabeculectomy was based on the procedure devised by Zimmerman et al.²⁰

Of the 49 Japanese patients with FAP, glaucoma was found in 20 eyes of 12 patients (24%). Molecular biological examinations showed Val30Met in 12 eyes of 7 patients, Tyr114Cys in 5 eyes of 3 patients, Ser50Ile in 1 eye of 1 patient, and a compound heterozygote of Val30Met + Arg104His in 2 eyes of 1 patient. In an attempt to elucidate the relationship between TTR mutations and the onset of glaucoma, we excluded the patient with the compound heterozygote from further statistical analysis. Analysis of the 48 patients with a single TTR mutation revealed that the incidence of glaucoma with Val30Met (7/41; 17%) was significantly lower than that with the other mutations (4/7; 57%) (P =.02 using the Fisher exact test) (Table 1).

Of the other ocular manifestations, abnormal conjunctival vessels were found in 60 eyes of 32 patients (61%), keratoconjunctivitis sicca in 59 eyes of 30 patients (60%), vitreous opacity in 35 eyes of 20 patients (35%), amyloid deposition along the pupil in 30 eyes of 18 patients (31%), fringed pupil in 8 eyes of 5 patients (8%), and glaucoma in 20 eyes of 12 patients (20%). Glaucoma was also diagnosed in all 8 eyes with a fringed pupil and in 17 (57%) of the 30 eyes with amyloid deposition on the pupil and/or anterior surface of the lens. Statistical analysis revealed a significant difference between the occurrence of glaucoma and amyloid deposition (P<.001 using the χ² test). In addition, glaucoma was present in 17(49%) of the 35 eyes with vitreous opacity (P<.001). On the other hand, there was no statistically significant relationship between the occurrence of glaucoma and abnormal conjunctival vessels, seen in 12 (20%) of the 60 eyes (P = .26), or the occurrence of glaucoma and keratoconjunctivitis sicca, seen in 15 (25%) of the 59 eyes (P = .78) (Table 2).

The mean ± SD follow-up period for the glaucomatous patients in our department was 4.27 ± 4.11 years (range, 0.1-12.0 years). In the 20 glaucomatous eyes, the occurrence of secondary glaucoma was found in both eyes of 8 patients and in 1 eye of 4 patients. The mean ± SD age at onset of glaucoma was 53.1 ± 7.9 years (range, 44-77 years). The mean ± SD period between the onset of systemic abnormalities caused by polyneuropathy and the onset of glaucoma was 7.01 ± 3.25 years (range, 0.5-12.3 years). In these 20 glaucomatous eyes, 18 eyes had amyloid deposition. Amyloid deposition was found prior to glaucoma in 11 eyes and at the first visit to our clinic in another 7 eyes, as indicated in Table 3. In the 11 eyes with an onset of amyloid deposition along the pupil prior to glaucoma, the mean ± SD period between the onsets of pupillary amyloid deposition and glaucoma was 2.55 ± 1.43 years(range, 0.2-4.0 years). The severity of visual field defects at the first visit to our department is also summarized in Table 3.²¹

In an attempt to control intraocular pressure, glaucoma surgery was performed for 15 of the 20 glaucomatous eyes (Table 3). Three of these 15 eyes had been operated on at other hospitals before the patients visited our department. In 1 (case 10) of these 3 eyes, cyclodestructive procedures were performed but resulted in visual loss caused by central retinal vein occlusion and subsequent neovascular glaucoma. In the remaining 2 eyes, trabeculectomy with MMC was performed. In one eye (case 8; right eye), neovascular glaucoma due to central retinal vein occlusion occurred, whereas in the other eye (case 12; right eye), an additional cyclodestructive procedure was required to control the intraocular pressure. In 12 of the 15 eyes that underwent surgery at our hospital, the operations performed were as follows: trabeculectomy with or without the intraoperative aid of MMC in 9 eyes (8 eyes with MMC and 1 eye without MMC), combined trabeculotomy and sinusotomy in 2 eyes, and nonpenetrating trabeculectomy in 1 eye. In the remaining 5 of the 20 glaucomatous eyes, in lieu of glaucoma surgery, antiglaucoma medication was prescribed. In 3 of these 5 eyes, although antiglaucoma medication could not maintain the intraocular pressure lower than the 20–mmHg level with a mean ± SD pressure of 25.0 ± 2.6 mmHg, we continued our observation and the use of antiglaucoma medication because of the systemic condition and lack of progression of visual field defects. In the other 2 eyes, the intraocular pressure was maintained at less than 20 mmHg.

The mean ± SD preoperative intraocular pressure was 35.0 ± 9.0 mmHg. In 10 (83%) of the 12 eyes operated on at our hospital, the intraocular pressure was well controlled at or lower than 20 mmHg during the follow-up periods (mean ± SD, 1.23 ± 1.79 years; range, 0.2-6.5 years). In all 9 eyes that underwent trabeculectomy, the intraocular pressure was well maintained and lower than the 20–mmHg level during the follow-up period. Postoperative treatment consisting of a needling procedure for bleb reconstruction in 1 eye (case 3; left eye) and a bleb patch for the cessation of aqueous leakage in 1 eye (case 1; right eye) was required. Hypotonic maculopathy occurred in 1 eye (case 4; left eye). In 1 of the 2 eyes that received trabeculotomy and sinusotomy, the intraocular pressure was well controlled and lower than 20 mmHg within the short follow-up period of 4 months (case 5). In another eye, nonpenetrating trabeculectomy was additionally performed because of unsatisfactory control of the intraocular pressure; however, this procedure also failed to lower the intraocular pressure, and finally trabeculectomy was performed (case 4; left eye). After nonpenetrating trabeculectomy was performed as the primary glaucoma surgery in 1 eye (case 8; left eye), the intraocular pressure was not well controlled, and an additional MMC-augmented trabeculectomy was performed 8 months after the primary surgery.

In 3 (25%) of the 12 glaucomatous patients with FAP, liver transplantation was performed for the treatment of systemic abnormalities. In 5 eyes of these 3 patients, glaucoma was found to occur even after liver transplantation. Furthermore, in all 5 glaucomatous eyes, deposition of ocular amyloid on the pupil border was observed. In 4 (80%) of the 5 glaucomatous eyes, amyloid deposition on the pupillary margin occurred after liver transplantation (Table 3).

Among known ocular complications in FAP, glaucoma is the major cause of vision loss in these patients. In this study, glaucoma was detected in 12 (24%) of 49 patients with FAP, although the incidence of ocular complications in the literature differs among various reports. For instance, in our previous study, ¹⁴ glaucoma was diagnosed in 2 (5.4%) of 37 patients with FAP, whereas Tsukahara and Matsuo¹¹ reported the incidence of glaucoma in patients with FAP to be 27%. The severity and improvement in treatment of systemic disorders in patients with FAP may lead to an increase in the incidence of ocular complications. This is especially true with regard to the recent development of liver transplantation for the treatment of patients with FAP, which can lead to longer life expectancies for these patients. However, because TTR can be produced within the eye, ^22,23 the production and deposition of FAP continues even after liver transplantation.^24-26 Thus, as a result of longer follow-up periods and longer patient life expectancies, the onset and progression of glaucoma have become a more frequent and serious ocular complication than previously documented before the advent of transplantation.

Multiple mechanisms seem to be involved in the cause of elevated intraocular pressure in patients with FAP. The deposition of perivascular amyloid in conjunctival and episcleral tissue may contribute to the elevation in episcleral venous pressure, resulting in an elevation in intraocular pressure.¹² Another possibility is that the deposition of ocular amyloid leads to a resultant obstruction in the aqueous outflow route.²⁷ We believe that the glaucoma associated with FAP is caused by these 2 mechanisms. Although elevation of episcleral venous pressure could not be documented in this study, we were able to detect a relationship between the deposition of ocular amyloid and the occurrence of glaucoma. In our study, we noted the deposition of ocular amyloid at the first examination or before the onset of glaucoma in 18 of 20 glaucomatous eyes. The 2 eyes that had glaucoma without amyloid deposition underwent vitrectomy and lensectomy at another hospital prior to the patients' first consultation with us, and thus the deposition of amyloid may have decreased as a result of those operations. Our results also showed a significant relationship between the onset of glaucoma and pupil abnormalities. The occurrence of glaucoma was confirmed in all 8 eyes with fringed pupils noted in this study. One patient with amyloid deposition developed glaucoma and a fringed pupil almost simultaneously. We hypothesize that the presence of a fringed pupil may be associated with a high amount of amyloid deposition on the pupil border. In addition, in all cases of fringed pupil, conspicuous deposition of ocular amyloid was observed on the pupil margin. Thus, the development of a fringed pupil may indicate the presence of a large amount of ocular amyloid.

In our study, TTR genetic mutation variants included Val30Met in 41 patients, Tyr114Cys in 6 patients, Ser50Ile in 1 patient, and a compound heterozygote of ATTR Val30Met + Arg104His in 1 patient. As previously stated, the Val30Met variant is the most common in Japanese patients. However, the clinical features of FAP in patients with the Val30Met mutation are somewhat different from those seen with other variants. For example, our experience shows that in patients with the Tyr114Cys variant, ocular complications including vitreous opacity will likely occur earlier than the onset of systemic disease and earlier than for patients with the Val30Met mutation.²⁸ In this study, the 17% incidence of glaucoma in patients with the Val30Met variant was significantly lower than the 57% incidence seen in patients with the other mutations (3 cases with Tyr114Cys, and 1 case with Ser50Ile). Considering the longer life expectancy due to the improvement in systemic treatment, the genetic differences associated with the occurrence of glaucoma may become more significant in the future.

Other ocular manifestations may also predict the onset of this vision-threatening disease. Among the many ocular complications that have been reported, amyloid deposition on the pupil border seems to be the most reliable ocular finding for predicting the onset of glaucoma. The deposition of ocular amyloid is almost always present prior to the onset of glaucoma, occurring several months to years before the diagnosis of glaucoma. Moreover, in our study, the onset of glaucoma was detected in all cases of fringed pupil. Vitreous opacity and pupillary amyloid deposition are highly related to the occurrence of glaucoma. In addition, although a significant association was observed between the occurrence of vitreous opacity and glaucoma, cases of vitreous opacity were not always followed by the onset of glaucoma. These 2 findings may be regarded as 2 different results derived from ocular manifestations of the deposited ocular amyloid. We have noted the progression of ocular manifestations caused by the deposition of amyloid as well as resultant glaucoma even after liver transplantation. This may be caused by the intraocular production of abnormal TTR variants.²³ In contrast, systemic disorders due to FAP can be treated or addressed, which results in longer life expectancies in these patients.²⁹ Thus, early diagnosis and careful treatment of glaucoma associated with FAP are more important than previously thought.

In our results, the intraocular pressure was well controlled and maintained at lower than 20 mmHg during the follow-up period in 10 (67%) of the 15 eyes that underwent operations. Unfortunately, our follow-up periods were not long enough to elucidate long-term surgical outcomes because of difficulties in performing follow-up examinations as a result of serious systemic disorders. However, as mentioned previously, because liver transplantation and other systemic treatments presently increase life expectancy, surgical treatment for glaucoma associated with FAP will be required in more patients.

Our experience with the surgical treatment of secondary glaucoma in patients with FAP reveals the application of MMC-augmented trabeculectomy to be the most promising treatment modality. We regard trabeculotomy as a surgical option for the treatment of adult-onset open-angle glaucoma.³⁰ Although our experience with trabeculotomy and nonpenetrating surgical procedures is limited, progressive deposition of ocular amyloid even after liver transplantation suggests that obstruction due to the deposited amyloid in the aqueous outflow route (surgically modified trabecular meshwork) can cause failure of the aqueous flow. Thus, at present we recommend MMC trabeculectomy as the primary surgical treatment for secondary glaucoma in patients with FAP.

In conclusion, our study documents the clinical features of secondary glaucoma in patients with FAP. Our results show that glaucoma is not a rare condition in patients with FAP. Careful examination for amyloid deposition along the pupil, as well as fringed pupil, allows the prediction of the onset of glaucoma. This is important because early detection is required to treat this ocular complication.

Submitted for publication December 11, 2001; final revision received November 1, 2002; accepted November 21, 2002.

This work was supported by Grant-in-Aid for Research 14370561 from the Ministry of Education, Science, Sports, and Culture, Tokyo, Japan.

Corresponding author and reprints: Akira Kimura, MD, PhD, Department of Ophthalmology, Kumamoto University School of Medicine, 1-1-1 Honjo, Kumamoto 860-8556, Japan (e-mail: akimura@gpo.kumamoto-u.ac.jp).