- Email: [email protected]
Conjunctival Biopsy in Infantile Neuroaxonal Dystrophy
Table. Relation Between Vitreous Cells and Retinal Tears in Asymptomatic or Not Recently Symptomatic Eyes Vitreous Celt Density
None Trace 1+ 2+ 3+ 4+ Total
Percent of Eyes With Tears
0.9% 4.5% 2.6% 25.0% 42.9% 0 2.6%
(4/440) (4/88) (1/38) (3/12) (3/7) (15/585)
or operculated retinal tear. Twenty-one eyes (3.6%) also had at least one atrophic round retinal hole without traction or local retinal detachment. These nontractional holes were not included in this analysis. Increased numbers of vitreous cells were associated with an increased likelihood that a retinal tear was present (Table). Of patients with 2+ or more cells (10 or more cells per 1-mm slit beam), 31.6% (6/19) had at least one retinal tear vs those with 1 + or fewer cells (one to nine cells per 1-mm slit-lamp field), of which 1.6% (9/566) had a tear (P = .0001, chi-square). This study implies that routinely performing slitlamp examination of the anterior vitreous in search of cells may help to identify asymptomatic eyes harbor ing retinal tears, especially if 2+ or more vitreous cells are present. However, only 40% of eyes (6/15) with tears had 2+ cells or more, and four tears (26.7%) had no associated cells. Tears without cells were generally small and did not expose much retinal pigment epithelium to the vitreous cavity, whereas larger tears tended to have more cells associated with them. It is possible that these eyes are not representative of all asymptomatic eyes because all were selected by referral, and all had a recently symptomatic fellow eye. However, the 2.6% of asymptomatic eyes that had a tear is similar to the 1.9% and 2.1% found in two large unselected series,4,5 implying that patients in this study may be representative of the general population. Examination of the anterior vitreous for cells can be performed quickly and easily. Because vitreous cells may indicate the presence of a retinal tear, slit-lamp examination of the anterior vitreous should
264
be performed in all patients undergoing a routine eye examination regardless of whether or not that patient has reported recent light flashes or floaters. Addition ally, because nine eyes with 1 + or fewer cells had a retinal tear, the absence of vitreous cells does not rule out the presence of a tear. REFERENCES 1. Hamilton AM, Taylor W. Significance of pigment granules in the vitreous. Br J Ophthalmol 1972;56:700-702. 2. Boldrey EE. Risk of retinal tears in patients with vitreous floaters. A m J Ophthalmol 1983;96:783-787. 3. Brod RD, Lightman DA, Packer AJ, Saras HP. Correlation between vitreous pigment granules and retinal breaks in eyes with acute posterior vitreous detachment. Ophthalmology 1991;98:1366-1369. 4. Byer NE. Clinical study of retinal breaks. Trans Am Acad Ophthalmol Otolaryngol 1967;71:461-472. 5. Foos RY. Postural peripheral retinal tears. A n n Ophthalmol 1974;6:679-687.
Conjunctival Biopsy in Infantile Neuroaxonal Dystrophy Rosane C. Ferreira, MD, Gary W. Mierau, PhD, and J. Bronwyn Bateman, MD PURPOSE: To describe a case of infantile neuroax onal dystrophy with optic nerve atrophy and to discuss the diagnostic role of conjunctival biopsy. METHODS: We performed a complete ophthalmologic examination and a diagnostic conjunctival biopsy on a girl with a neurodegenerative disease. RESULTS: On the basis of "spheroid" inclusions in the unmyelinated axons, we diagnosed infantile neuoroaxonal dystrophy. CONCLUSIONS: Optic atrophy is an important finding in infantile neuroaxonal dystrophy, and conjunctival biopsy is a reliable and very conve nient diagnostic test.
Accepted for publication Sept 20, 1996. Departments of Ophthalmology (R.C.F., J.B.B.) and Pathology (G.W.M.), The Children's Hospital, University of Colorado; and Depart ment of Ophthalmology, Federal University of Sao Paulo (R.C.F.). Inquiries to ]. Bronwyn Bateman, MD, Department of Ophthal mology, University of Colorado Health Sciences Center, Box B204, 4200 E Ninth Ave, Denver, CO 80262; fax: (303) 315-5644; e-mail: [email protected]
AMERICAN JOURNAL OF OPHTHALMOLOGY
FEBRUARY
1997
I
NFANTILE NEUROAXONAL DYSTROPHY, INITIALLY DE-
scribed by Seitelberger1 in 1952, is a rare, progressive neurologic disease with autosomal recessive inheri tance (also known as Seitelberger disease). The disease is characterized pathologically by widespread distribution of terminal axonal swellings called "spheroids" in both the central and peripheral ner vous systems.2 Onset occurs between ages 6 months and 2 years and includes psychomotor deterioration, symmetric pyramidal tract signs, and marked hypotonia.3 The course of the disease is progressive, and epileptic seizures, myoclonic jerks, and extrapyramidal signs may develop.3 Visual impairment is evi dent clinically.4 Strabismus, pendular nystagmus, and incoordinate eye movements occur early.3 Optic atrophy is described in 40% of cases by age 3 years.3 Results of electroretinographic examination are re portedly normal.3,4 Until 25 years ago, brain biopsy and postmortem examination were the only means of diagnosing infantile neuroaxonal dystrophy. Because no bio chemical defect has been identified and the clinical symptomatology is not pathognomonic, infantile neu roaxonal dystrophy can only be reliably recognized by electron microscopic examination for enlarged ax ons.2'4 Ultrastructural study of motor endplates and endomysial axons can support the diagnosis.2 We confirmed that conjunctival biopsy is a useful diag nostic tool in infantile neuroaxonal dystrophy. The patient was a 2-year-10-month-old girl of nonconsanguineous parents, with no family history of neurologic disease. Pregnancy and delivery were un complicated, and the patient's early developmental milestones were normal. After 6 months of age, the child regressed; she was never able to stand or walk. A diagnosis of a progressive neurodegenerative disease was made. The child was admitted to the hospital for diagnostic and ophthalmologic examinations. She was visually inattentive and had intermittent nystag mus. By slit-lamp biomicroscopy, we noted severe blepharitis in both eyes. O n ophthalmoscopic exami nation, optic disks were pale. Under topical anesthe sia, an uncomplicated conjunctival biopsy was per formed in the office; a 1.5-mm-long and 1.0-mm-wide sample was taken from the inferotemporal bulbar conjunctiva and submitted in toto for ultrastructural evaluation.
VOL.123, No. 2
Figure. Electron micrograph showing a large filamentous "spheroid" inclusion in an unmyelinated axon (arrow) (uranil acetate/lead citrate X22,400). Electron microscopic examination of the conjunc tival biopsy specimen failed to disclose any unusual lysosomal storage product within endothelial cells, pericytes, Schwann cells, fibroblasts, or keratocytes. Within a small proportion of unmyelinated axons, "spheroid" inclusions characteristic of infantile neu roaxonal dystrophy were evident (Figure). These displayed either a tubulovesicular or a filamentous substructure, with occasional clear clefts. Within both unmyelinated and myelinated axons, distinctive accumulations of degenerate mitochondria and other organelles associated with this entity were evident. Infants with infantile neuroaxonal dystrophy ex hibit normal psychomotor development until age 1 year; thereafter, progressive mental deterioration, ataxia, and hypotonia are evident. Later, the cerebellar features are progressively masked by increasing pyramidal syndrome, decerebration rigidity, and bul bar and sphincter disturbances. The duration of the disease varies from 3 to 10 years.3 Neuropathologic features include numerous system atrophies, axonal spheroids, and sudanophilic leukodystrophy.3 Eyes are affected in almost one half of patients.3 Present in up to 40% of cases,3 optic atrophy is the most common finding. Aicardi and Castelein3 re viewed 50 cases of infantile neuroaxonal dystrophy in the neurologic literature and found only five patients who were free of visual symptoms. Seven patients had amaurosis, seven had nystagmus, two had strabismus, and 44 patients experienced decreased vision because
BRIEF REPORTS
265
of optic nerve atrophy. To our knowledge, we are reporting the second case of infantile neuroaxonal dystrophy with optic atrophy in the ophthalmic literature. Infantile neuroaxonal dystrophy is the first neurodegenerative disorder outside the group of lysosomal storage diseases for which the skin or conjunctiva diagnostic approach is useful.2,5 Aicardi and Castelein3 described difficulties in neuropathologic analysis of infantile neuroaxonal dystrophy by conjunctival biopsy. For example, in routine preparations, spheroids cannot be seen by light microscopy, and thus, finding spheroids in axons may be a timeconsuming process. Crisci and associates5 confirmed that studying biopsy specimens of conjunctiva in patients with infantile neuroaxonal dystrophy is timeconsuming. Additionally, biopsy specimens may pro vide insufficient fibers for analysis because nerve fibers are unevenly distributed in the conjunctiva. In this study, conjunctival biopsy was useful in diagnosing a case of infantile neuroaxonal dystrophy. REFERENCES 1. Seitelberger F. Erne unbekannte form von infantiler lipoid Speicher-Krankheit des Gehirn. In: Proceedings of the First Congress of Neuropathology, Rome. Volume 3. Turin: Rosen berg and Sellier, 1952:323-333. 2. Martin J], Leroy JG, Libert J, van Eygen M, Logghe N. Skin and conjunctival biopsies in infantile neuroaxonal dystrophy. Acta Neuropathol 1979;45:247-251. 3. Aicardi J, Castelein P. Infantile neuroaxonal dystrophy. Brain 1979;102:727-748. 4. Goebel HH, Lehmann J. An ultrastructural study of the retina in human late infantile neuroaxonal dystrophy. Retina 1993;13:50-55. 5. Crisci C, Gomez MR, Hohberger GG, Giannini C, Dyck PJ. Is conjunctival biopsy useful for diagnosis of neuroaxonal dystro phy? [letter] Ann Neurol 1989;26:691.
Conjunctival Metastasis From a Cutaneous Melanoma as the Initial Sign of Dissemination
METHOD: An excisional biopsy of an amelanotic pedunculated conjunctival lesion in a 52-year-old man showed epithelioid melanoma. RESULTS: Systemic examination showed wide spread disseminated disease from a cutaneous melanoma that had been removed 3 Vi years earlier. At that time, no signs of metastatic disease were detected. Despite chemotherapy, the patient died 6 weeks later. CONCLUSION: Conjunctival metastasis from a cutaneous melanoma is a rare and ominous sign of widely disseminated disease.
O
CULAR METASTASIS FROM CUTANEOUS MALIG-
nant melanoma is well documented, especially when it occurs to the uveal tract and occasionally to the retina, vitreous, optic nerve, and orbit.1'4 Very few reports, however, discuss cutaneous malignant mela noma metastatic to the conjunctiva, and in all previous cases, the patients studied had known meta static disease.1 To our knowledge, we report the only case of a conjunctival metastasis from a cutaneous malignant melanoma in which the conjunctival le sion was the first detected site of metastatic disease. We examined a 52-year-old man with a 5 X 5 X 4-mm vascularized, amelanotic, pedunculated lesion arising from the palpebral conjunctiva of the left lower eyelid (Figure 1). The remainder of his ocular examination results were unremarkable. Excisional biopsy of the lesion was performed, and pathologic ex amination disclosed malignant melanoma of the epi thelioid type with no evidence of intraepithelial melanocytic change or superficial nevus cells (Figure 2). The patient's primary physician informed us that 3Vi years earlier, the patient had had a 2 X 1.5-cm, slightly raised, brown nodule removed from the right side of his neck. The patient was unsure how long the lesion had existed. The excisional biopsy measured 3 x 2 x 2 cm, and histologic evaluation of this lesion had disclosed a nodular polypoid malignant melano ma invading to a depth of 7 mm (Clarke level 4). The
Bradley R. Kwapiszeski, MD, and Michael L. Savitt, MD PURPOSE: We report a case in which a conjuncti val metastasis from a cutaneous melanoma was the first sign of metastatic disease.
266
Accepted for publication Sept 19, 1996. Department of Ophthalmology, Loyola University Chicago. Inquiries to Bradley R. Kwapiszeski, MD, Shawnee Mission Eye Care, PA, 8901 W 74th St, Ste 285, Shawnee Mission, KS 66204; fax: (913) 362-0407.
AMERICAN JOURNAL OF OPHTHALMOLOGY
FEBRUARY 1997
None Trace 1+ 2+ 3+ 4+ Total
Percent of Eyes With Tears
0.9% 4.5% 2.6% 25.0% 42.9% 0 2.6%
(4/440) (4/88) (1/38) (3/12) (3/7) (15/585)
or operculated retinal tear. Twenty-one eyes (3.6%) also had at least one atrophic round retinal hole without traction or local retinal detachment. These nontractional holes were not included in this analysis. Increased numbers of vitreous cells were associated with an increased likelihood that a retinal tear was present (Table). Of patients with 2+ or more cells (10 or more cells per 1-mm slit beam), 31.6% (6/19) had at least one retinal tear vs those with 1 + or fewer cells (one to nine cells per 1-mm slit-lamp field), of which 1.6% (9/566) had a tear (P = .0001, chi-square). This study implies that routinely performing slitlamp examination of the anterior vitreous in search of cells may help to identify asymptomatic eyes harbor ing retinal tears, especially if 2+ or more vitreous cells are present. However, only 40% of eyes (6/15) with tears had 2+ cells or more, and four tears (26.7%) had no associated cells. Tears without cells were generally small and did not expose much retinal pigment epithelium to the vitreous cavity, whereas larger tears tended to have more cells associated with them. It is possible that these eyes are not representative of all asymptomatic eyes because all were selected by referral, and all had a recently symptomatic fellow eye. However, the 2.6% of asymptomatic eyes that had a tear is similar to the 1.9% and 2.1% found in two large unselected series,4,5 implying that patients in this study may be representative of the general population. Examination of the anterior vitreous for cells can be performed quickly and easily. Because vitreous cells may indicate the presence of a retinal tear, slit-lamp examination of the anterior vitreous should
264
be performed in all patients undergoing a routine eye examination regardless of whether or not that patient has reported recent light flashes or floaters. Addition ally, because nine eyes with 1 + or fewer cells had a retinal tear, the absence of vitreous cells does not rule out the presence of a tear. REFERENCES 1. Hamilton AM, Taylor W. Significance of pigment granules in the vitreous. Br J Ophthalmol 1972;56:700-702. 2. Boldrey EE. Risk of retinal tears in patients with vitreous floaters. A m J Ophthalmol 1983;96:783-787. 3. Brod RD, Lightman DA, Packer AJ, Saras HP. Correlation between vitreous pigment granules and retinal breaks in eyes with acute posterior vitreous detachment. Ophthalmology 1991;98:1366-1369. 4. Byer NE. Clinical study of retinal breaks. Trans Am Acad Ophthalmol Otolaryngol 1967;71:461-472. 5. Foos RY. Postural peripheral retinal tears. A n n Ophthalmol 1974;6:679-687.
Conjunctival Biopsy in Infantile Neuroaxonal Dystrophy Rosane C. Ferreira, MD, Gary W. Mierau, PhD, and J. Bronwyn Bateman, MD PURPOSE: To describe a case of infantile neuroax onal dystrophy with optic nerve atrophy and to discuss the diagnostic role of conjunctival biopsy. METHODS: We performed a complete ophthalmologic examination and a diagnostic conjunctival biopsy on a girl with a neurodegenerative disease. RESULTS: On the basis of "spheroid" inclusions in the unmyelinated axons, we diagnosed infantile neuoroaxonal dystrophy. CONCLUSIONS: Optic atrophy is an important finding in infantile neuroaxonal dystrophy, and conjunctival biopsy is a reliable and very conve nient diagnostic test.
Accepted for publication Sept 20, 1996. Departments of Ophthalmology (R.C.F., J.B.B.) and Pathology (G.W.M.), The Children's Hospital, University of Colorado; and Depart ment of Ophthalmology, Federal University of Sao Paulo (R.C.F.). Inquiries to ]. Bronwyn Bateman, MD, Department of Ophthal mology, University of Colorado Health Sciences Center, Box B204, 4200 E Ninth Ave, Denver, CO 80262; fax: (303) 315-5644; e-mail: [email protected]
AMERICAN JOURNAL OF OPHTHALMOLOGY
FEBRUARY
1997
I
NFANTILE NEUROAXONAL DYSTROPHY, INITIALLY DE-
scribed by Seitelberger1 in 1952, is a rare, progressive neurologic disease with autosomal recessive inheri tance (also known as Seitelberger disease). The disease is characterized pathologically by widespread distribution of terminal axonal swellings called "spheroids" in both the central and peripheral ner vous systems.2 Onset occurs between ages 6 months and 2 years and includes psychomotor deterioration, symmetric pyramidal tract signs, and marked hypotonia.3 The course of the disease is progressive, and epileptic seizures, myoclonic jerks, and extrapyramidal signs may develop.3 Visual impairment is evi dent clinically.4 Strabismus, pendular nystagmus, and incoordinate eye movements occur early.3 Optic atrophy is described in 40% of cases by age 3 years.3 Results of electroretinographic examination are re portedly normal.3,4 Until 25 years ago, brain biopsy and postmortem examination were the only means of diagnosing infantile neuroaxonal dystrophy. Because no bio chemical defect has been identified and the clinical symptomatology is not pathognomonic, infantile neu roaxonal dystrophy can only be reliably recognized by electron microscopic examination for enlarged ax ons.2'4 Ultrastructural study of motor endplates and endomysial axons can support the diagnosis.2 We confirmed that conjunctival biopsy is a useful diag nostic tool in infantile neuroaxonal dystrophy. The patient was a 2-year-10-month-old girl of nonconsanguineous parents, with no family history of neurologic disease. Pregnancy and delivery were un complicated, and the patient's early developmental milestones were normal. After 6 months of age, the child regressed; she was never able to stand or walk. A diagnosis of a progressive neurodegenerative disease was made. The child was admitted to the hospital for diagnostic and ophthalmologic examinations. She was visually inattentive and had intermittent nystag mus. By slit-lamp biomicroscopy, we noted severe blepharitis in both eyes. O n ophthalmoscopic exami nation, optic disks were pale. Under topical anesthe sia, an uncomplicated conjunctival biopsy was per formed in the office; a 1.5-mm-long and 1.0-mm-wide sample was taken from the inferotemporal bulbar conjunctiva and submitted in toto for ultrastructural evaluation.
VOL.123, No. 2
Figure. Electron micrograph showing a large filamentous "spheroid" inclusion in an unmyelinated axon (arrow) (uranil acetate/lead citrate X22,400). Electron microscopic examination of the conjunc tival biopsy specimen failed to disclose any unusual lysosomal storage product within endothelial cells, pericytes, Schwann cells, fibroblasts, or keratocytes. Within a small proportion of unmyelinated axons, "spheroid" inclusions characteristic of infantile neu roaxonal dystrophy were evident (Figure). These displayed either a tubulovesicular or a filamentous substructure, with occasional clear clefts. Within both unmyelinated and myelinated axons, distinctive accumulations of degenerate mitochondria and other organelles associated with this entity were evident. Infants with infantile neuroaxonal dystrophy ex hibit normal psychomotor development until age 1 year; thereafter, progressive mental deterioration, ataxia, and hypotonia are evident. Later, the cerebellar features are progressively masked by increasing pyramidal syndrome, decerebration rigidity, and bul bar and sphincter disturbances. The duration of the disease varies from 3 to 10 years.3 Neuropathologic features include numerous system atrophies, axonal spheroids, and sudanophilic leukodystrophy.3 Eyes are affected in almost one half of patients.3 Present in up to 40% of cases,3 optic atrophy is the most common finding. Aicardi and Castelein3 re viewed 50 cases of infantile neuroaxonal dystrophy in the neurologic literature and found only five patients who were free of visual symptoms. Seven patients had amaurosis, seven had nystagmus, two had strabismus, and 44 patients experienced decreased vision because
BRIEF REPORTS
265
of optic nerve atrophy. To our knowledge, we are reporting the second case of infantile neuroaxonal dystrophy with optic atrophy in the ophthalmic literature. Infantile neuroaxonal dystrophy is the first neurodegenerative disorder outside the group of lysosomal storage diseases for which the skin or conjunctiva diagnostic approach is useful.2,5 Aicardi and Castelein3 described difficulties in neuropathologic analysis of infantile neuroaxonal dystrophy by conjunctival biopsy. For example, in routine preparations, spheroids cannot be seen by light microscopy, and thus, finding spheroids in axons may be a timeconsuming process. Crisci and associates5 confirmed that studying biopsy specimens of conjunctiva in patients with infantile neuroaxonal dystrophy is timeconsuming. Additionally, biopsy specimens may pro vide insufficient fibers for analysis because nerve fibers are unevenly distributed in the conjunctiva. In this study, conjunctival biopsy was useful in diagnosing a case of infantile neuroaxonal dystrophy. REFERENCES 1. Seitelberger F. Erne unbekannte form von infantiler lipoid Speicher-Krankheit des Gehirn. In: Proceedings of the First Congress of Neuropathology, Rome. Volume 3. Turin: Rosen berg and Sellier, 1952:323-333. 2. Martin J], Leroy JG, Libert J, van Eygen M, Logghe N. Skin and conjunctival biopsies in infantile neuroaxonal dystrophy. Acta Neuropathol 1979;45:247-251. 3. Aicardi J, Castelein P. Infantile neuroaxonal dystrophy. Brain 1979;102:727-748. 4. Goebel HH, Lehmann J. An ultrastructural study of the retina in human late infantile neuroaxonal dystrophy. Retina 1993;13:50-55. 5. Crisci C, Gomez MR, Hohberger GG, Giannini C, Dyck PJ. Is conjunctival biopsy useful for diagnosis of neuroaxonal dystro phy? [letter] Ann Neurol 1989;26:691.
Conjunctival Metastasis From a Cutaneous Melanoma as the Initial Sign of Dissemination
METHOD: An excisional biopsy of an amelanotic pedunculated conjunctival lesion in a 52-year-old man showed epithelioid melanoma. RESULTS: Systemic examination showed wide spread disseminated disease from a cutaneous melanoma that had been removed 3 Vi years earlier. At that time, no signs of metastatic disease were detected. Despite chemotherapy, the patient died 6 weeks later. CONCLUSION: Conjunctival metastasis from a cutaneous melanoma is a rare and ominous sign of widely disseminated disease.
O
CULAR METASTASIS FROM CUTANEOUS MALIG-
nant melanoma is well documented, especially when it occurs to the uveal tract and occasionally to the retina, vitreous, optic nerve, and orbit.1'4 Very few reports, however, discuss cutaneous malignant mela noma metastatic to the conjunctiva, and in all previous cases, the patients studied had known meta static disease.1 To our knowledge, we report the only case of a conjunctival metastasis from a cutaneous malignant melanoma in which the conjunctival le sion was the first detected site of metastatic disease. We examined a 52-year-old man with a 5 X 5 X 4-mm vascularized, amelanotic, pedunculated lesion arising from the palpebral conjunctiva of the left lower eyelid (Figure 1). The remainder of his ocular examination results were unremarkable. Excisional biopsy of the lesion was performed, and pathologic ex amination disclosed malignant melanoma of the epi thelioid type with no evidence of intraepithelial melanocytic change or superficial nevus cells (Figure 2). The patient's primary physician informed us that 3Vi years earlier, the patient had had a 2 X 1.5-cm, slightly raised, brown nodule removed from the right side of his neck. The patient was unsure how long the lesion had existed. The excisional biopsy measured 3 x 2 x 2 cm, and histologic evaluation of this lesion had disclosed a nodular polypoid malignant melano ma invading to a depth of 7 mm (Clarke level 4). The
Bradley R. Kwapiszeski, MD, and Michael L. Savitt, MD PURPOSE: We report a case in which a conjuncti val metastasis from a cutaneous melanoma was the first sign of metastatic disease.
266
Accepted for publication Sept 19, 1996. Department of Ophthalmology, Loyola University Chicago. Inquiries to Bradley R. Kwapiszeski, MD, Shawnee Mission Eye Care, PA, 8901 W 74th St, Ste 285, Shawnee Mission, KS 66204; fax: (913) 362-0407.
AMERICAN JOURNAL OF OPHTHALMOLOGY
FEBRUARY 1997