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Ocular Findings Associated with Neurofibromatosis Type II
Ocular Findings Associated with N eurofibromatosis Type II Laurence D. Kaye, MD, A. David Rothner, MD, George R. Beauchamp, MD, Sanford M. Meyers, MD, Melinda L. Estes, MD
Background: Neurofibromatosis has been recently acknowledged as consisting of a number of different diseases. Neurofibromatosis (NF) type I and NF type II are the most clearly defined. Type II is characterized by bilateral acoustic neuromas and is rare (its incidence is 1/50,000). The previously reported ocular associations of NF type II are posterior subcapsular cataracts, Lisch nodules, and combined hamartomata of the retinal pigment epithelium and retina. In this study, the authors attempt to define further the ocular manifestations of NF type II. Methods: The authors prospectively examined 9 patients who met the diagnostic criteria for NF type II (age, 18 to 38 years; mean, 25 years). Results: Seven of nine patients had epiretinal membranes in the posterior pole. None of these epiretinal membranes were visually significant. In addition, five patients had central posterior cortical cataracts and five had peripheral wedge-shaped cortical cataracts. Conclusion: The presence of epiretinal membranes in young patients may represent another clinical finding associated with NF type II. Epiretinal membranes, central posterior cataracts, peripheral cortical cataracts, or combined hamartoma of the retinal epithelium and retina in young patients should alert the ophthalmologist to include NF type II in the differential diagnosis in patients with stigmata of NF type II. Ophthalmology 1992;99: 1424-1429
Neurofibromatosis (NF) was first reviewed by von Recklinghausen I in 1882. In 1987, NF type II, formerly central neurofibromatosis, was shown to be a distinct disorder inherited in an autosomal dominant fashion, transmitted to offspring by a gene on human chromosome 22. The incidence of NF type II is 1 in 50,000.2 The mutation rate is unknown. The diagnostic criteria for NF type II are: bilateral eighth nerve masses or a unilateral eighth nerve mass and a first-degree relative with bilateral eighth nerve masses. Neurofibromatosis type II is associated with
Originally received: December 4, 1991. Revision accepted: April 7, 1992. From the Departments of Ophthalmology, Neurology, and Pathology, The Cleveland Clinic Foundation, Cleveland. Presented in part at the AUPOS Meeting, Montreal, Canada, May 1991 , and at The Cleveland Clinic Resident's Day Conference, June 1991. Reprint requests to Laurence D. Kaye, MD, Texas Tech Health Sciences Center, School of Medicine, Department of Ophthalmology, Lubbock, TX 79430.
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numerous intracranial and intraspinal tumors.2 The only ocular associations reported are posterior subcapsular cataracts, 3 retinal hamartomata,4.5 and one case of unilateral Lisch nodules. 6 The purpose of this study is to examine prospectively NF type II patients for associated ocular findings.
Materials and Methods We prospectively examined nine patients who met the clinical criteria for the diagnosis of NF type 11. 2 Patients 7 and 8 were sister and brother; all other cases were sporadic. All patients received complete neurologic and ophthalmic examinations. Documentation of previous tumors in these nine patients was obtained from surgical, pathologic, and radiologic reports (Table I). During the course of the study, one patient died. A complete autopsy was performed, including histopathologic examination of the globes. Serial 8-J.Lm paraffinembedded sections were stained with hematoxylin-eosin.
Kaye et al . Ocular Findings Associated with Neurofibromatosis Table 1. Patient Characteristics No.
Sex
Age (yrs)
1
M
2
Patient
Eye Findings
Other Tumors
38
Lisch nodules, OS Peripheral cortical cataract, OD Epiretinal membrane, OS (superotemporal parafoveal area)
F
22
Epiretinal meVlbrane, OS (temporal parafoveal area)
3
F
33
4
F
24
5
F
23
6
F
19
7
F
19
Enucleation OD for painful optic nerve meningioma Central posterior cortical cataract, OD (pathology report) Central posterior cortical cataract, OS Peripheral cortical cataract, OS Epiretinal membrane, OS (temporal parafoveal area) Central posterior cortical and posterior subcapsular cataracts,OU Multiple retinal astrocytomas, OD with subsequent exudative retinal detachment and phthisis Epiretinal membrane, OS (along superotemporal arcade) (histopathology revealed membrane to be glial) Central posterior cortical cataracts, OU Epiretinal membranes, OS (superior parafoveal and inferior parafoveal) Papilledema, OS Peripheral cortical cataract, OS (removed at age 6) Epiretinal membranes, OU (OD inferior parafoveal) (OS along superotemporal arcade) Amblyopia, OD (history of exotropia) Epiretinal membrane, OD (temporal parafoveal)
Multiple intramedullary and extramedullary spinal tumors Left third nerve meningioma Bilateral fifth nerve tumors Abdominal wall -schwannoma Right tibial nerve schwannoma Orbital plexiform neurolemmoma Scalp neurofibroma Posterior auricular schwannoma Left foot neurofibroma Right foot neurofibroma Abdominal neurofibroma Cervical spinal neurofibroma Thoracic meningioma Right optic nerve meningioma Multiple spinal and intracranial tumors
8
M
18
Peripheral cortical cataracts, OU Central posterior cortical cataract, OD
9
F
32
Central posterior cortical cataracts, OU Peripheral cortical cataracts, OU Papilledema
os =
left eye; OD
=
right eye; OU
=
Left lumbar schwannoma Right cerebellopontine meningioma Posterior fossa meningioma Right cervical meningioma
Sural plexiform neurofibroma Spinal cord meningioma Intradural schwannoma Spinal cord schwannoma Cervical spine neurofibroma Trigeminal neuroma Multiple spinal tumors Dural meningioma Bilateral trigeminal meningiomas Multiple spinal cord tumors (intramedullary and extramedullary) Multiple spinal neurofibromas Left mid cranial fossa meningioma Thoracic ependymoma Posterior fossa meningioma Cervical cord ependymoma Parietal lobe meningioma Right shoulder neurolemmoma Peripheral nerve schwannoma
both eyes.
Selected sections were immunostained for glial fibrillary acid protein with a modified avidin-biotin complex technique. 7 Electron microscopy was performed on an epiretinal membrane identified in the cadaver's left eye. This tissue was fixed in glutaraldehyde, and thin sections of approximately 0.5 ~m were cut from selected blocks and stained with uranyl acetate-lead citrate for electron microscopy.
Results Nine patients met the diagnostic criteria for NF type II; none met the criteria for NF type I. Seven patients were female and two were male. The patients ranged in age from 18 to 38 years (mean, 25 years) (Table 1). Seven of nine patients had epiretinal membranes within
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Volume 99, Number 9, September 1992
Top left, Figure 1. Patient 1, left eye. A translucent epiretinal macula membrane with prominent whitish edges and inferior and temporal parafoveal retinal stria. Top right, Figure 2. Patient 2, left eye. Tongue~like projection of translucent epiretinal macula membrane in the temporal parafoveal area at age 14. Center left, Figure 3. Patient 2, left eye. Intravenous fluorescein an· giogram shows loss of detail of retinal vessel secondary to overlying epiretinal membrane. There was no leakage or stain below the epi· retinal membrane. Center right, Figure 4. Patient 3, left eye. Semitranslucent epiretinal macula membrane with whitish areas over foveal and parafoveal area with no underlying distortion. Bottom, Figure 5. Patient 4, left eye. Glial fibrillary acid protein stain of glial hamartoma with overlying epiretinal membrane (original magnification, X 1(0).
the temporal arcades (Table 1). Visual acuity was not affected by the epiretinal membranes, and there were no subjective complaints of metamorphopsia. All the membranes appeared to be epiretinal on biomicroscopic examination (patient 1, Fig 1). The membranes ranged in
1426
size from 1 to 3 disc diameters and were translucent with whitish edges. No patients had clinically observed foveal edema or shallow traction detachment of the fovea, although intravenous fluorescein angiography was performed on only one patient. The epiretinal membrane of
Kaye et al . Ocular Findings Associated with Neurofibromatosis
Figure 6. Patient 4, left eye. Electron micrograph of epiretinal membrane indicates spindle-shaped cell with cytoplasmic filaments (original magnification, x 14,300).
this patient (patient 2) had been photographed 8 years before and had not changed (Fig 2), and the fluorescein angiography showed no leakage or abnormal retinal vascularity (Fig 3). Patient 2 had a mild pigment disturbance superior to the fovea as well as some whitish-yellow lesions at the level of the retinal pigment epithelium superior to the fovea. These lesions are greater than 500 ~m away from the epiretinal membrane, and we did not believe that they were related to the epiretinal membrane. The epiretinal membrane in patient 3 is shown in Figure 4. Patient"4 died of multiple intracranial tumors. She had a history of multiple retinal astrocytomas in her right eye, which were complicated by secondary exudative detachment of the retina, which progressed to phthisis. Histopathologic examination of this eye confirmed phthisis bulbi. Clinical examination of the patient's left eye, before
her death, showed a central posterior cortical and a posterior subcapsular cataract. A dense epiretinal membrane along the superotemporal arcade also was seen. This measured approximately 2 disc diameters in size and was more dense than those seen in the other patients with NF type II. Histopathologic examination of her left eye showed a central posterior cortical cataract, a posterior subcapsular cataract, and an area of intraretinal glial proliferation with an overlying epiretinal membrane along the superotemporal arcade. The membrane was composed of astrocytic cells and stained positively for glial fibrillary acid protein (Fig 5). Electron microscopic examination of the epiretinal membrane in this patient confirmed the light microscopic finding of astrocytic cells. Spindle-shaped cells containing abundant cytoplasmic filaments measuring 10 ~m in diameter were seen (Fig 6). Of the nine patients, three had both central posterior cataracts and wedge-shaped cortical cataracts (Fig 7). Two patients had central posterior cataracts, and two patients had wedge-shaped peripheral cortical cataracts (Table 1). The mean age of the patients with peripheral cortical cataracts was 28 years. The posterior cataracts were densely granular in nature in one patient, involving the posterior cortical and the posterior subcapsular area. In three patients, there was a well-demarcated area of fine granularity in the central posterior cortical area not involving the posterior subcapsular area. One patient had histopathologic evidence of central posterior cortical cataract formation after enucleation of the right eye for a painful optic nerve meningioma. There was no mention of an epiretinal membrane on the pathologic report, which was prepared at another institution. One patient had cataract surgery at age six for a cortical cataract. Additional isolated ocular findings were optic nerve meningioma, chronic papilledema secondary to intracranial tumors, exotropia and amblyopia, and unilateral Lisch nodules (Fig 8) (Table 1).
left, Figure 7. Patient 9, right eye. Wedge-shaped peripheral cortical cataract by retroillumination. Right, Figure 8. Patient 1, left eye. Unilateral Lisch nodules.
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Volume 99, Number 9, September 1992
Discussion Epiretinal membranes in the posterior pole were present in seven of the nine patients. Epiretinal membranes may occur during the course of several ocular disorders, including proliferative vitreoretinopathy, ocular inflammation, retinal vascular disease, trauma, vitreous hemorrhage, rhegmatogenous retinal detachment, after retinal photocoagulation or cryotherapy, and as an idiopathic process in otherwise normal eyes. 8,9 Epiretinal membranes were not described in a series of NF type I patients. 10 There have been recent reports of combined hamartoma of the retinal pigment epithelium and retina in NF type IL 4 ,11,12 Epiretinal membrane formation is a recognized association of combined hamartoma of the retinal pigment epithelium and retina. In the case reported by Good et aV the epiretinal macular lesion in the patient's left eye appeared similar to the epiretinal membranes seen in our series. Combined hamartoma of the retinal pigment epithelium and retina was first described in 1973 by Gass I3 as a slightly elevated, variably pigmented lesion associated with surface retinal disturbance and vascular tortuosity. Schachat and associates '4 have proposed that there is a spectrum of lesions in combined hamartoma of the retinal pigment epithelium and retina, ranging from vascular malformations alone at one end to epiretinal membranes at the other. Two thirds of their patients had visual loss attributable to these lesions. In our series, no patients had visual loss attributable to epiretinal membranes. Patient 4 had intraretinal glial proliferation with an overlying epiretinal membrane on histopathologic examination. The positive glial fibrillary acid protein stain and the electron microscopy suggest that the intraretinal astrocytic proliferation may represent an early glial hamartoma. IS None of the other eight patients had clinical features of combined hamartoma of the retinal pigment epithelium and retina as described by Gass. 13 The clinical appearance of the epiretinal membrane in the left eye of patient 4 was more dense and more opaque than the other epiretinal membranes in our study. Therefore, the histopathologic finding in this eye may not be representative of epiretinal membranes in NF type II, but further clinicopathologic studies are needed to establish the relationship between epiretinal membranes and combined hamartoma of the retinal pigment epithelium and retina in NF type II. Epiretinal membranes were present in seven of nine NF type II patients and may represent another ocular finding associated with NF type II. The presence of the epiretinal membrane in patient 2 was noted when her bilateral acoustic neuromas were diagnosed at age 14. The chronologic relationship of the epiretinal membranes to acoustic neuromas is not known, and further studies will be required to identify this relationship. Lewis and Riccardi 10 reviewed the ocular findings in 77 patients with NF type I. They specifically excluded NF type II patients (then called central neurofibromatosis). They reported no cases of epiretinal membranes in these NF type I patients. The association of posterior subcapsular lens opacities with bilateral acoustic neuromas has been established by
1428
Kaiser-Kupfer et al. 3 Our patients had posterior central cortical cataracts (4 of 9), posterior central cortical and posterior subcapsular cataracts (1 of 9), and peripheral cortical cataracts (5 of9). Our findings, together with those described by Kaiser-Kupfer et aI, suggest that posterior central cataracts in NF type II can involve either the posterior central cortical region or the posterior subcapsular area. The occurrence of peripheral wedge-shaped cortical lens opacities in five of our patients is of interest in view of their youth. The relatively high incidence of such cataracts suggests a possible association with NF type II. Kaiser-Kupfer et al 3 noted other types of cataracts in two of nine patients with NF type II. The presence of unilateral Lisch nodules in one patient is of interest. The strict diagnostic criteria for neurofibromatosis suggest that Lisch nodules are an exclusive feature of NF type I. Charles et al,6 however, also described a patient with NF type II who had unilateral Lisch nodules and no other features of NF type I. They suggest that, as both NF type I and NF type II are disorders of neural crest tissue, there is no reason why Lisch nodules could not occur in NF type II. Lisch nodules are generally bilateral in adults with NF type 1.10 However, in both the patient reported on by Charles et al and in our patient, the Lisch nodules were unilateral. Preservation of hearing and facial nerve function have been the goals of surgical resection of acoustic neuromas. Although this has been difficult, particularly for patients with bilateral tumors, case reports using modern neuroimaging and the intraoperative use of brainstem auditory-evoked responses have described early diagnosis and subsequent successful resection with preservation of hearing. '6- '8 The only apparent good prognostic indicator is small tumor size, which makes the early diagnosis of NF type II critical. The importance of early diagnosis further emphasizes the need to identify clinical findings associated with NF type II. The presence of an epiretinal membrane, central posterior cataracts, peripheral cortical cataracts, or combined hamartoma of the retinal pigment epithelium and retina in a young patient should alert the ophthalmologist to include NF type II in the differential diagnosis in patients with stigmata of NF type II.
References 1. von Recklinghausen FD. Ueber die multiplen Fibrome der Haut und ihre Beziehung zu den multiplen Neuromen. Berlin: Hirschwald, 1882, 2, National Institutes of Health. Neurofibromatosis. [Bethesda, MDl: The Institutes, 1987. (National Institutes of Health Consensus Development Conference Statement; v.6, no. 12). 3. Kaiser-Kupfer MI, Freidlin V, Datiles MB, et al. The association of posterior capsular lens opacities with bilateral acoustic neuromas in patients with neurofibromatosis type 2. Arch Ophthalmol 1989;107:541-4. 4. Good WV, Brodsky MC, Edwards MS, Hoyt WF. Bilateral retinal hamartomas in neurofibromatosis type 2. Br J Ophthalmo! 1991;75:190. 5. Martyn U, Knox DL. Glial hamartoma of the retina in
Kaye et al . Ocular Findings Associated with Neurofibromatosis
6. 7. 8. 9.
10. 11.
generalized neurofibromatosis. von Recklinghausen's disease. Br J Ophthalmol 1972;56:487-91. Charles SJ, Moore AT, Yates JRW, Ferguson-Smith MA. Lisch nodules in neurofibromatosis type 2 [letter]. Arch Ophthalmol 1989; 107: 1571-2. Hsu SM, Raine L, Fanger H. The use of antiavidin antibody and avidin-biotin-peroxidase complex in immunoperoxidase technics. Am J Clin Pathol 1981;75:816-21. Kampik A, Kenyon KR, Michels RG, et ai. Epiretinal and vitreous membranes. Comparative study of 56 cases. Arch Ophthalmol 1981 ;99: 1445-54. Smiddy WE, Maguire AM, Green WR, et al. Idiopathic epiretinal membranes: ultrastructural characteristics and clinicopathologic correlation. Ophthalmology 1989;96:81121. Lewis RA, Riccardi VM. von Recklinghausen neurofibromatosis incidence of iris hamartomata. Ophthalmology 1981 ;88:348-54. Landau K, Dossetor FM, Hoyt WF, Muci-Mendoza R. Retinal hamartoma in neurofibromatosis 2 [letter]. Arch Ophthalmol 1990; 108:328-9.
12. Cotlier E. Cafe-au-Iait spots of the fundus in neurofibromatosis. Arch Ophthalmol 1977;95: 1990-2. 13. Gass JDM. An unusual hamartoma of the pigment epithelium and retina simulating choroidal melanoma and retinoblastoma. Trans Am Ophthalmal Soc 1973;71: 171-85. 14. Schachat AP, Shields JA, Fine SL, et al. Combined hamartomas of the retina and retinal pigment epithelium. Ophthalmology 1984;91: 1609-15. 15. Green WR. Retina. In: Spencer WH, ed. Ophthalmic Pathology: An Atlas and Textbook, 3rd ed. Vol. 2. Philadelphia: WB Saunders, 1985;617-8. 16. Martuza RL, Ojemann RG. Bilateral acoustic neuromas: clinical aspects, pathogenesis, and treatment. Neurosurgery 1982;10:1-12. 17. Miyamoto RT, Campbell RL, Fritsch M, Lochmueller G. Preservation of hearing in neurofibromatosis 2. Otolaryngo1 Head Neck Surg 1990;103:619-24. 18. Martuza RL, Eldridge R. Neurofibromatosis 2 (bilateral acoustic neurofibromatosis). N Engl J Med 1988;318:684-
8.
1429
Background: Neurofibromatosis has been recently acknowledged as consisting of a number of different diseases. Neurofibromatosis (NF) type I and NF type II are the most clearly defined. Type II is characterized by bilateral acoustic neuromas and is rare (its incidence is 1/50,000). The previously reported ocular associations of NF type II are posterior subcapsular cataracts, Lisch nodules, and combined hamartomata of the retinal pigment epithelium and retina. In this study, the authors attempt to define further the ocular manifestations of NF type II. Methods: The authors prospectively examined 9 patients who met the diagnostic criteria for NF type II (age, 18 to 38 years; mean, 25 years). Results: Seven of nine patients had epiretinal membranes in the posterior pole. None of these epiretinal membranes were visually significant. In addition, five patients had central posterior cortical cataracts and five had peripheral wedge-shaped cortical cataracts. Conclusion: The presence of epiretinal membranes in young patients may represent another clinical finding associated with NF type II. Epiretinal membranes, central posterior cataracts, peripheral cortical cataracts, or combined hamartoma of the retinal epithelium and retina in young patients should alert the ophthalmologist to include NF type II in the differential diagnosis in patients with stigmata of NF type II. Ophthalmology 1992;99: 1424-1429
Neurofibromatosis (NF) was first reviewed by von Recklinghausen I in 1882. In 1987, NF type II, formerly central neurofibromatosis, was shown to be a distinct disorder inherited in an autosomal dominant fashion, transmitted to offspring by a gene on human chromosome 22. The incidence of NF type II is 1 in 50,000.2 The mutation rate is unknown. The diagnostic criteria for NF type II are: bilateral eighth nerve masses or a unilateral eighth nerve mass and a first-degree relative with bilateral eighth nerve masses. Neurofibromatosis type II is associated with
Originally received: December 4, 1991. Revision accepted: April 7, 1992. From the Departments of Ophthalmology, Neurology, and Pathology, The Cleveland Clinic Foundation, Cleveland. Presented in part at the AUPOS Meeting, Montreal, Canada, May 1991 , and at The Cleveland Clinic Resident's Day Conference, June 1991. Reprint requests to Laurence D. Kaye, MD, Texas Tech Health Sciences Center, School of Medicine, Department of Ophthalmology, Lubbock, TX 79430.
1424
numerous intracranial and intraspinal tumors.2 The only ocular associations reported are posterior subcapsular cataracts, 3 retinal hamartomata,4.5 and one case of unilateral Lisch nodules. 6 The purpose of this study is to examine prospectively NF type II patients for associated ocular findings.
Materials and Methods We prospectively examined nine patients who met the clinical criteria for the diagnosis of NF type 11. 2 Patients 7 and 8 were sister and brother; all other cases were sporadic. All patients received complete neurologic and ophthalmic examinations. Documentation of previous tumors in these nine patients was obtained from surgical, pathologic, and radiologic reports (Table I). During the course of the study, one patient died. A complete autopsy was performed, including histopathologic examination of the globes. Serial 8-J.Lm paraffinembedded sections were stained with hematoxylin-eosin.
Kaye et al . Ocular Findings Associated with Neurofibromatosis Table 1. Patient Characteristics No.
Sex
Age (yrs)
1
M
2
Patient
Eye Findings
Other Tumors
38
Lisch nodules, OS Peripheral cortical cataract, OD Epiretinal membrane, OS (superotemporal parafoveal area)
F
22
Epiretinal meVlbrane, OS (temporal parafoveal area)
3
F
33
4
F
24
5
F
23
6
F
19
7
F
19
Enucleation OD for painful optic nerve meningioma Central posterior cortical cataract, OD (pathology report) Central posterior cortical cataract, OS Peripheral cortical cataract, OS Epiretinal membrane, OS (temporal parafoveal area) Central posterior cortical and posterior subcapsular cataracts,OU Multiple retinal astrocytomas, OD with subsequent exudative retinal detachment and phthisis Epiretinal membrane, OS (along superotemporal arcade) (histopathology revealed membrane to be glial) Central posterior cortical cataracts, OU Epiretinal membranes, OS (superior parafoveal and inferior parafoveal) Papilledema, OS Peripheral cortical cataract, OS (removed at age 6) Epiretinal membranes, OU (OD inferior parafoveal) (OS along superotemporal arcade) Amblyopia, OD (history of exotropia) Epiretinal membrane, OD (temporal parafoveal)
Multiple intramedullary and extramedullary spinal tumors Left third nerve meningioma Bilateral fifth nerve tumors Abdominal wall -schwannoma Right tibial nerve schwannoma Orbital plexiform neurolemmoma Scalp neurofibroma Posterior auricular schwannoma Left foot neurofibroma Right foot neurofibroma Abdominal neurofibroma Cervical spinal neurofibroma Thoracic meningioma Right optic nerve meningioma Multiple spinal and intracranial tumors
8
M
18
Peripheral cortical cataracts, OU Central posterior cortical cataract, OD
9
F
32
Central posterior cortical cataracts, OU Peripheral cortical cataracts, OU Papilledema
os =
left eye; OD
=
right eye; OU
=
Left lumbar schwannoma Right cerebellopontine meningioma Posterior fossa meningioma Right cervical meningioma
Sural plexiform neurofibroma Spinal cord meningioma Intradural schwannoma Spinal cord schwannoma Cervical spine neurofibroma Trigeminal neuroma Multiple spinal tumors Dural meningioma Bilateral trigeminal meningiomas Multiple spinal cord tumors (intramedullary and extramedullary) Multiple spinal neurofibromas Left mid cranial fossa meningioma Thoracic ependymoma Posterior fossa meningioma Cervical cord ependymoma Parietal lobe meningioma Right shoulder neurolemmoma Peripheral nerve schwannoma
both eyes.
Selected sections were immunostained for glial fibrillary acid protein with a modified avidin-biotin complex technique. 7 Electron microscopy was performed on an epiretinal membrane identified in the cadaver's left eye. This tissue was fixed in glutaraldehyde, and thin sections of approximately 0.5 ~m were cut from selected blocks and stained with uranyl acetate-lead citrate for electron microscopy.
Results Nine patients met the diagnostic criteria for NF type II; none met the criteria for NF type I. Seven patients were female and two were male. The patients ranged in age from 18 to 38 years (mean, 25 years) (Table 1). Seven of nine patients had epiretinal membranes within
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Ophthalmology
Volume 99, Number 9, September 1992
Top left, Figure 1. Patient 1, left eye. A translucent epiretinal macula membrane with prominent whitish edges and inferior and temporal parafoveal retinal stria. Top right, Figure 2. Patient 2, left eye. Tongue~like projection of translucent epiretinal macula membrane in the temporal parafoveal area at age 14. Center left, Figure 3. Patient 2, left eye. Intravenous fluorescein an· giogram shows loss of detail of retinal vessel secondary to overlying epiretinal membrane. There was no leakage or stain below the epi· retinal membrane. Center right, Figure 4. Patient 3, left eye. Semitranslucent epiretinal macula membrane with whitish areas over foveal and parafoveal area with no underlying distortion. Bottom, Figure 5. Patient 4, left eye. Glial fibrillary acid protein stain of glial hamartoma with overlying epiretinal membrane (original magnification, X 1(0).
the temporal arcades (Table 1). Visual acuity was not affected by the epiretinal membranes, and there were no subjective complaints of metamorphopsia. All the membranes appeared to be epiretinal on biomicroscopic examination (patient 1, Fig 1). The membranes ranged in
1426
size from 1 to 3 disc diameters and were translucent with whitish edges. No patients had clinically observed foveal edema or shallow traction detachment of the fovea, although intravenous fluorescein angiography was performed on only one patient. The epiretinal membrane of
Kaye et al . Ocular Findings Associated with Neurofibromatosis
Figure 6. Patient 4, left eye. Electron micrograph of epiretinal membrane indicates spindle-shaped cell with cytoplasmic filaments (original magnification, x 14,300).
this patient (patient 2) had been photographed 8 years before and had not changed (Fig 2), and the fluorescein angiography showed no leakage or abnormal retinal vascularity (Fig 3). Patient 2 had a mild pigment disturbance superior to the fovea as well as some whitish-yellow lesions at the level of the retinal pigment epithelium superior to the fovea. These lesions are greater than 500 ~m away from the epiretinal membrane, and we did not believe that they were related to the epiretinal membrane. The epiretinal membrane in patient 3 is shown in Figure 4. Patient"4 died of multiple intracranial tumors. She had a history of multiple retinal astrocytomas in her right eye, which were complicated by secondary exudative detachment of the retina, which progressed to phthisis. Histopathologic examination of this eye confirmed phthisis bulbi. Clinical examination of the patient's left eye, before
her death, showed a central posterior cortical and a posterior subcapsular cataract. A dense epiretinal membrane along the superotemporal arcade also was seen. This measured approximately 2 disc diameters in size and was more dense than those seen in the other patients with NF type II. Histopathologic examination of her left eye showed a central posterior cortical cataract, a posterior subcapsular cataract, and an area of intraretinal glial proliferation with an overlying epiretinal membrane along the superotemporal arcade. The membrane was composed of astrocytic cells and stained positively for glial fibrillary acid protein (Fig 5). Electron microscopic examination of the epiretinal membrane in this patient confirmed the light microscopic finding of astrocytic cells. Spindle-shaped cells containing abundant cytoplasmic filaments measuring 10 ~m in diameter were seen (Fig 6). Of the nine patients, three had both central posterior cataracts and wedge-shaped cortical cataracts (Fig 7). Two patients had central posterior cataracts, and two patients had wedge-shaped peripheral cortical cataracts (Table 1). The mean age of the patients with peripheral cortical cataracts was 28 years. The posterior cataracts were densely granular in nature in one patient, involving the posterior cortical and the posterior subcapsular area. In three patients, there was a well-demarcated area of fine granularity in the central posterior cortical area not involving the posterior subcapsular area. One patient had histopathologic evidence of central posterior cortical cataract formation after enucleation of the right eye for a painful optic nerve meningioma. There was no mention of an epiretinal membrane on the pathologic report, which was prepared at another institution. One patient had cataract surgery at age six for a cortical cataract. Additional isolated ocular findings were optic nerve meningioma, chronic papilledema secondary to intracranial tumors, exotropia and amblyopia, and unilateral Lisch nodules (Fig 8) (Table 1).
left, Figure 7. Patient 9, right eye. Wedge-shaped peripheral cortical cataract by retroillumination. Right, Figure 8. Patient 1, left eye. Unilateral Lisch nodules.
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Volume 99, Number 9, September 1992
Discussion Epiretinal membranes in the posterior pole were present in seven of the nine patients. Epiretinal membranes may occur during the course of several ocular disorders, including proliferative vitreoretinopathy, ocular inflammation, retinal vascular disease, trauma, vitreous hemorrhage, rhegmatogenous retinal detachment, after retinal photocoagulation or cryotherapy, and as an idiopathic process in otherwise normal eyes. 8,9 Epiretinal membranes were not described in a series of NF type I patients. 10 There have been recent reports of combined hamartoma of the retinal pigment epithelium and retina in NF type IL 4 ,11,12 Epiretinal membrane formation is a recognized association of combined hamartoma of the retinal pigment epithelium and retina. In the case reported by Good et aV the epiretinal macular lesion in the patient's left eye appeared similar to the epiretinal membranes seen in our series. Combined hamartoma of the retinal pigment epithelium and retina was first described in 1973 by Gass I3 as a slightly elevated, variably pigmented lesion associated with surface retinal disturbance and vascular tortuosity. Schachat and associates '4 have proposed that there is a spectrum of lesions in combined hamartoma of the retinal pigment epithelium and retina, ranging from vascular malformations alone at one end to epiretinal membranes at the other. Two thirds of their patients had visual loss attributable to these lesions. In our series, no patients had visual loss attributable to epiretinal membranes. Patient 4 had intraretinal glial proliferation with an overlying epiretinal membrane on histopathologic examination. The positive glial fibrillary acid protein stain and the electron microscopy suggest that the intraretinal astrocytic proliferation may represent an early glial hamartoma. IS None of the other eight patients had clinical features of combined hamartoma of the retinal pigment epithelium and retina as described by Gass. 13 The clinical appearance of the epiretinal membrane in the left eye of patient 4 was more dense and more opaque than the other epiretinal membranes in our study. Therefore, the histopathologic finding in this eye may not be representative of epiretinal membranes in NF type II, but further clinicopathologic studies are needed to establish the relationship between epiretinal membranes and combined hamartoma of the retinal pigment epithelium and retina in NF type II. Epiretinal membranes were present in seven of nine NF type II patients and may represent another ocular finding associated with NF type II. The presence of the epiretinal membrane in patient 2 was noted when her bilateral acoustic neuromas were diagnosed at age 14. The chronologic relationship of the epiretinal membranes to acoustic neuromas is not known, and further studies will be required to identify this relationship. Lewis and Riccardi 10 reviewed the ocular findings in 77 patients with NF type I. They specifically excluded NF type II patients (then called central neurofibromatosis). They reported no cases of epiretinal membranes in these NF type I patients. The association of posterior subcapsular lens opacities with bilateral acoustic neuromas has been established by
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Kaiser-Kupfer et al. 3 Our patients had posterior central cortical cataracts (4 of 9), posterior central cortical and posterior subcapsular cataracts (1 of 9), and peripheral cortical cataracts (5 of9). Our findings, together with those described by Kaiser-Kupfer et aI, suggest that posterior central cataracts in NF type II can involve either the posterior central cortical region or the posterior subcapsular area. The occurrence of peripheral wedge-shaped cortical lens opacities in five of our patients is of interest in view of their youth. The relatively high incidence of such cataracts suggests a possible association with NF type II. Kaiser-Kupfer et al 3 noted other types of cataracts in two of nine patients with NF type II. The presence of unilateral Lisch nodules in one patient is of interest. The strict diagnostic criteria for neurofibromatosis suggest that Lisch nodules are an exclusive feature of NF type I. Charles et al,6 however, also described a patient with NF type II who had unilateral Lisch nodules and no other features of NF type I. They suggest that, as both NF type I and NF type II are disorders of neural crest tissue, there is no reason why Lisch nodules could not occur in NF type II. Lisch nodules are generally bilateral in adults with NF type 1.10 However, in both the patient reported on by Charles et al and in our patient, the Lisch nodules were unilateral. Preservation of hearing and facial nerve function have been the goals of surgical resection of acoustic neuromas. Although this has been difficult, particularly for patients with bilateral tumors, case reports using modern neuroimaging and the intraoperative use of brainstem auditory-evoked responses have described early diagnosis and subsequent successful resection with preservation of hearing. '6- '8 The only apparent good prognostic indicator is small tumor size, which makes the early diagnosis of NF type II critical. The importance of early diagnosis further emphasizes the need to identify clinical findings associated with NF type II. The presence of an epiretinal membrane, central posterior cataracts, peripheral cortical cataracts, or combined hamartoma of the retinal pigment epithelium and retina in a young patient should alert the ophthalmologist to include NF type II in the differential diagnosis in patients with stigmata of NF type II.
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