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Vitreous hemorrhage as an ophthalmic complication of galactosemia
922
Levy et al.
The Journal of Pediatrics December 1996
Vitreous hemorrhage as an ophthalmic complication of galactosemia Harvey L. Levy, MD, Anne E. Brown, JD, Steven E. Williams, MD, and Eugene de Juan, Jr., MD From the Division of Genetics, Children's Hospital and the Department of Pediatrics, Harvard Medical School, Boston, Massachusetts; Doherty, Rumble & Butler Professional Association, Attorneys at Law, St. Paul, Minnesota; and The Wilmer Ophthalmological Institute, Johns Hopkins Hospital, Baltimore, Maryland
A major complication of galactosemia is cataracts. This is usually considered to be the sole ophthalmic feature of this disorder. However, we have encountered vitreous hemorrhage, a very rare ophthalmic finding, in five neonates with galactosemia and have found four probable additional cases in the literature. All of these infants had severe neonatal manifestations of galactosemia and were discovered to have vitreous hemorrhage by ophthalmologic examination initiated by the observation of clouding of the eye or on a routine basis. The infants lost most or all vision from the affected eye. Retinal abnormalities were present in the involved eyes of the five neonates of whom we have direct knowledge. Thus we believe that retinal hemorrhage is the most likely source of the vitreous hemorrhage and that the coagulopathy associated with neonatal disease in galactosemia leads to vitreous hemorrhage. Prompt recognition and therapy for the coagulopathy would likely prevent vitreous hemorrhage in galactosemia. (J Pediatr 1996; 129:922-5) Galactosemia is a metabolic disorder caused by a defect in galactose 1-phosphate uridyltransferase, one of three enzymes required to fully metabolize galactose (Figure). It occurs with a frequency of approximately 1:62,000 in the general population. 1 Neonates with this inborn error who breast-feed or are fed a regular infant milk formula accumulate galactose 1-phosphate and galactose from the galactose liberated from milk lactose by intestinal lactase (Figure). The elevated levels of galactose 1-phosphate produce neonatal illness characterized by vomiting, jaundice, fiver dysfunction, weight loss, and "oil droplet" cataract. 2 Prompt withdrawn of milk results in rapid reversal of these features, whereas delay in treatment places the infant at high risk of bacterial sepsis and meningitis with resulting neonatal death or irreversible neurologic disease. 3' 4 Cirrhosis and mental retardation develop in most untreated children with galactosemia who survive the neonatal period, 5 and almost all have cataracts, 6 usually considered to be the sole ophthalmic complication of this disorder. Submitted for publication Feb. 12, 1996; accepted July 3, 1996. Reprint requests: Harvey L. Levy, MD, I.C. Smith 106, Children's Hospital, 300 Longwood Ave., Boston, MA 02115. Copyright © 1996 by Mosby-Year Book, Inc. 0022-3476/96/$5.00 + 0 9/22/?6244
We report vitreous hemorrhage, a rare ophthalmic finding7, 8 in five infants with galactosemia. In addition, we call attention to four probable additional cases from the literature. We believe that vitreous hemorrhage is an ophthalmic complication of galactosemia hitherto unrecognized. CASE REPORTS Patient 1. A 3470 female infant of 40 weeks' gestation was delivered by spontaneous vaginal delivery and had Apgar scores of 9 at 1 minute and 10 at 5 minutes. Physical examination revealed an alert, nonjanndiced infant with equal, reactive pupils, and bilateral red reflexes on ophthalmoscopy. She was discharged home 1 day after birth and received a milk formula after 2 days of breast-feeding. At 9 days of age, the infant was brought to the hospital emergency department. Her weight had decreased to 2900 gm, she had vomiting and diarrhea, her skin was noticeably icteric with redundant skin folds, and she was described as being somnolent. She also had hepatomegaly, elevated total and direct serum bilirubin levels, and abnormal liver function (Table I). Although the infant was noted to have multiple small bruises associated with venous access sites, studies for coagulopathy were not done, and the hematocrit and platelets were normal (Table I). Urinalysis revealed a positive finding for reducing substance. The diagnosis of galactosemia was made, and the infant was admitted for dietary restriction and metabolic support. The admitting physician noted possible corneal clouding of the
The Journal of Pediatrics Volume 129, Number 6
Intestine
Levy et al.
923
Liver
Figure. Liberation of galactose from lactose in the intestine and its metabolism. The enzymes required for galactose metabolism are galactokinase (]), galactose 1-phosphate uridyltransferase (2), and uridine diphosphate-4-epimerase (3). In galactosemia, the defective enzyme is galactose 1-phosphate uridyltransferase.
left eye, and follow-up examination during the hospitalization revealed the infant had a vitreous hemorrhage of the left eye. Three months later she underwent a vitrectomy for a nonclearing vitreous hemorrhage. The intraoperative findings are presented in Table II. The prognosis for vision in the left eye is poor. Patient 2. A 3250 gm boy delivered at 39 weeks of gestation by spontaneous vaginal delivery had Apgar scores of 8 at 1 minute and 9 at 5 minutes. Newborn examinations performed by the pediatrician and nurse indicated normal eyes. Initial feeding included breast milk supplemented by a milk formula. At 9 days of age, the boy was admitted to the neonatal intensive care unit because of poor feeding and poor weight gain. Examination revealed a diminished weight of 2800 gin, jaundice, hepatomegaly, and blood oozing from previous venipuncture sites. Laboratory analysis revealed elevated total and direct serum bilirubin levels, markedly abnormal results of fiver function studies, decreased platelet counts, prolonged prothrombin and partial thromboplastin times, and a low fibrinogen level (Table I). Urinalysis disclosed 4+ reducing substance and absent erythroeyte galactose 1-phosphate uridyltransferase activity. The diagnosis of galactosemia was made, and the patient was given a nonlactose formula. Platelet and fresh frozen plasma transfusions were given to reverse the coagulopathy. Clouding of the right eye was noted at 10 days of age. Ophthalmologic examination revealed reactive pupils and clear lenses but vitreous hemorrhage of the right eye. A vitrectomy of the right eye was performed at 3 weeks of age. The intraoperative examination findings are presented in Table II. Later, at 6 weeks of age, examination with the patient under anesthesia for possible cataract extraction of the right eye revealed severe retinal scarfing with traction elevation in all quadrants. The prognosis for vision in the right eye is poor.
Patient 3. A 1400 gm male infant was delivered by cesarean section at 31 weeks of gestation with Apgar scores of 6 at 1 minute and 9 at 5 minutes. The neonatologist reported the corneas to be clear and the presence of a red reflex bilaterally. A second neonatologist also reported the eyes to be normal. The infant was breastfed. At 9 days of age, his weight had decreased to 1380 gin, he bad jaundice with an enlarged liver, and bruising of the right foot. During the next 3 days, the bilirubin levels increased despite phototherapy (Table I), and cyanosis, temperature instability, lethargy, mad diarrhea developed. At 12 days of age, the blood galactose Levelwas reported as elevated, and a subsequent markedly elevated blood galactose l-phosphate level confirmed the diagnosis of galactosemia. Breast-feeding was discontinued and the infant was fed a nonlactose formula. His condition rapidly hnaproved; he was discharged at 1 month of age. At 5 weeks of age, during a routine examination for retinopathy of prematurity, the infant was noted to have vitreous haze and a diagnosis of vitreous hemorrhage was made. A follow-up examination with the patient under anesthesia was performed at 4 months of age. The results of the examination are presented in Table II. Although he is considered legally blind, this child has some functional vision. This case has been reported in abstract form by Buist et al.9 Patient 4. A 4400 gm male infant was delivered by forcepsassisted vaginal delivery at 41 weeks of gestation; the infant had Apgar scores of 9 at 1 minute and 10 at 5 minutes. Results of ocular examinations on newborn admission and discharge were normal. The infant was breast-fed initially but feeding problems resulted in use of a milk formula. At 10 days of age, a nonlactose formula was started because of continued feeding problems. At 18 days of age, the diagnosis of galactosemia was confirmed by newborn screening and the infant had an ophthalrnologie exam-
924
Levy et al.
The Journal of Pediatrics December 1996
Table I. Laboratory values in the infants with galactosemia and vitreous hemorrhage Age of diagnosis (days) Case
Galactosemia
Vitreous hemorrhage
1 2 3 4 5
9 9 12 10 36
10 10 38 17 58
Prothrombin/partial thromboplastin time (seconds)
Hematocrit (%)/ platelets (in thousands)
Alanine aminotransferase/ aspartate aminotransferase (U/L)
Bilirubin (total/direct) (mg/dl)
Not done 23.4/14.3 Not done Not dont 16.7/117
59.3/210 50.6/38 45.3/385 Not done 30/254
123/129 140/140 Not done Not done 92/196
18.2/3.8 17.2/0.9 11.4/0.7 Not done 24.9/1.1
Table II. Intraoperative ocular findings in galactosemic infants with vitreous hemorrhage Case I (left eye only)
Case 2 (right eye only)
Case 3 (both eyes)
Dense vitreous hemorrage with fibrinous response Markedly sclerotic retinal vessels Thick epiretinal membrane (assumed to be the posterior hyaloid) present over surface of retina Scattered intraretinal punctate deposits Small retinal fold extending along supertemporal and inferotemporal arcades Macula appeared "flat"
Dense tan and red vitreous hemorrhage Dense packing of RBCs on the posterior lens capsule Severe subretinal scarfing in temporal and inferior retina extending to fovea (resolving subretinal hemorrhage) Scarfing and residual subretinal blood in far periphery superiorly and nasally
Right eye (examination with infant under anesthesia) Central serous retinal elevation Macular scarfing Dense midperipheral scarfing Left eye (examination with infant under anesthesia) Dense vitreous stranding Dense vitreous band obscured clear view of macula but no macular scarring noted Dense midperipheral retinal scarring with very dense retinal haze and band formation
Case 4 (right eye only) Dense vitreous hemorrhage (straw-colored "sheets" of RBCs) Posterior hyaloid detached over the retinal pole Nasal portion of retina hemorrhagic
Case 5 (left eye only) Dense vitreous hemorrhage (ochre-colored) Attenuation of retinal arterioles Optic nerve and macula dragged temporally Submacular and temporal subretinal blood Hyperpigmented cells on retinal surface
RBCs, Red blood cells.
ination. This revealed no apparent pupillary defect but mild cataracts of both eyes and no red reflex of the right eye. A diagnosis of probable vitreous hemorrhage was made and observation for clearing of the hemorrhage was planned. However, 6 days later the infant was admitted to the hospital with multifocal septic arthritis and osteomyelitis caused by Escherichia coll. When ultrasonography of the right eye revealed persistent vitreous debris, the diagnosis of endogenous endophthalmitis was considered. Microscopic examination of the vitreous contents revealed many erythrocytes but only rare leukocytes. A vitrectomy in the right eye was performed. The intraoperative findings are presented in Table II. At 14 weeks of age, retinal hyperpigmentation had replaced the hemorrhage. At age 6fi years, the child's visual acuity was 20/50 in both eyes with persistent right esotropia and nystagmus. Patient g. A 3440 gm boy was born by uncomplicated spontaneous vaginal delivery at 38 weeks of gestation. Apgar scores were 7 at 1 minute and 9 at 5 minutes. The neonatal admission and dis-
charge examination noted intact red reflexes bilaterally. The infant was breast-fed. At 5 weeks of age, a physical examination revealed failure to regain birth weight, jaundice, hepatomegaly, prolonged bleeding from venipuncture sites, and bilateral absence of red reflexes. Laboratory studies disclosed hyperbilirubinemia, markedly abnormal liver function test results, and prolonged prothrombin and partial thromboplastin times (Table I). When the urinalysis revealed reducing substance and a galactose level of 900 mg/dl, the diagnosis of galactosemia was made. Ophthalmic evaluation at 5 weeks of age revealed bilateral cataracts. After the infant's medical status was stable, extracapsular cataract extraction of the left eye was performed. Intraoperatively a vitreous hemorrhage was foun& Subsequently vitrectomy for nonclearing vitreous hemorrhage was performed. The intraoperafive findings are presented in Table II. The prognosis for vision in the left eye is poor.
The Journal of Pediatrics Volume 129, Number 6
DISCUSSION This report documents vitreous hemorrhage in five neonates with galactosemia. In addition, we have found four previously re,ported cases of galactosemia in which vitreous hemorrhage was probably also present. 5' 10 Vitreous hemorrhage is rare in neonates and is usually associated with perinatal complications]' 8 Only one of the five infants with galactosemia we describe had perinatal difficulties, indicating that vitreous hemorrhage in these infants was most likely a complication of galactosemia. We believe that hemorrhage from retinal vessels is probably the source of the vitreous blood. The five infants in our case reports had retinal abnormalities ranging from hemorrhages to subretinal scarring, the latter likely associated with a resolving hemorrhage. Although retinal hemorrhage in the neonate is "very frequent, occurring in 25% to 37% of infants born by vaginal delivery, 11-13 the typical neonatal retinal hemorrhage usually resolves by 10 days of age without leaving residual damage. 14 More serious hemorrhage into the vitreous and subretinal space is very rare without other evidence of disease or injury. In the patients with galactosemia whom we describe, the hemorrhages were all severe and did not appear to be related to the typical benign neonatal intraretinal hemorrhage. Although very unlikely, it is possible that hemorrhage from neovascularized areas of the choroid could result in vitreous bleeding. Moreover, retinal vessels overlying the optic disc may hemorrhage through the disc, as can hemorrhages from deep in the parenchyma of the optic nerve. The vitreous hemorrhage in these infants with galactosemia is likely to have resulted from the coagulopathy associated with untreated galactosemia. The two infants in whom coagulation factors were examined had prolonged prothrombin and partial thromboplastin times (Table I). One of these infants (Case 2) also had a reduced fibrinogen level. Braises and prolonged bleeding at venipuncture sites, or both, were noted in two of the other three infants. Korson et al.15 have found that coagulopathy is one of the most frequent early findings in neonates with galactosemia and may be present with otherwise little evidence of liver disease. Supporting the likelihood that coagulopathy in galactosemia is the antecedent to vitreous hemorrhage is the disseminated intravascular coagulopathy in several of the reported cases of infants without galactosemia who sustained vitreous hemorrhage. 7, s Fragility of the retinal vessels in the neonate, perhaps exacerbated by galactosemia, is most likely a major contributing factor to the vitreous hemorrhage in the presence of coagulopathy.
Levy et al.
925
Delay in diagnosis and treatment of galactosemia in the neonate to beyond the first week of life results in substantial coagulopathy.I5 Thus vitreous hemorrhage can probably be largely prevented in this disorder by early diagnosis and withdrawal from milk together with prompt attention to the possibility of coagulopatby and administration of fresh frozen plasma when coagulopathy is detected. We thank the parents who so willingly allowed us to obtain this information. REFERENCES
I. Levy HL, Hammersen G. Newborn screening for galactosemia and other galactose metabolic defects. J Pediatr 1978;92:871-7. 2. Segal S, Berry GT. Disorders of galactose metabolism. In: Scriver CR, Beaudet AL, Sly WS, Valle D, editors. The metabolic and molecular bases of inherited disease. 7tb ed. New York: McGraw-Hill, 1995:967-1000. 3. Donnell GN, Koch R, Fishler K, Ng WG. Clinical aspects of galactosemia. In: Burman D, Holton JB, Pennock CA, editors. Inherited disorders of carbohydrate metabolism. Baltimore: University Park, 1980:103-15. 4. Levy HL, Sepe SJ, Shih VE, Vawter GF, Klein JO. Sepsis due to Escherichia coli in neonates with galactosemia. N Engl J Med 1977;297:823-5. 5. Hsia DY-Y, Walker FA. Variability in the clinical manifestations of galactosemia. J Pediatr 1961;59:872-83. 6. Burke JP, O'Keefe M, Bowell R, Naughten ER. Ophthalmic findings in classical galactosemia--a screened population. J Pediatr Ophthalmol Strabismus 1989;26:165-8. 7. Ferrone PJ, de Juan E. Vitreous hemorrhage in infants. Arch Ophthalmol 1994;1 l 2:1185-9. 8. Wiznia RA, Price J. Vitreous hemorrhage and disseminated intravascular coagulation in the newborn. Am J Ophthalmol 1976;82:222-6. 9. Buist NRM, Waggoner DD, Tuerck JM. Six galactosemic patients with serious vitreal and retinal lesions [abstract]. Toledo, Spain: Society for the Study of Inborn Errors of Metabolism, Sept 12-15, 1995:221. 10. Vangsted P. Galactosemia with cataract and persistent hyaloid artery. Acta Ophthalmol 1980;58:812-8. 11. Jain IS, Singh YP, Grupta SL, Gupta A. Ocular hazards during birth. J Pediatr Ophthalrnol Strabismus 1980;17:14-6. 12. Levin S, Janive J, Mintz M, Kreisler C, Romen M, Klutznik A, et al. Diagnostic and prognostic value of retinal hemorrhages in the neonate. Obstet Gynecol 1980;55:309-14. 13. Williams MC, Knuppel RA, O'Brien WF, Weiss A, Spellacy WN, Pietrantoni M. Obstetric correlates of neonatal retinal hemorrhage. Obstet Gynecol 1993;81:688-94. 14. Isenberg SJ. Ocular trauma. In: Isenberg SJ, editor. The eye in infancy. Chicago: Year Book, 1989:377-85. 15. Korson M, Irons M, Levy HL. The neonatal phenotype of galactosemia [abstract]. Pediatr Res 1987;21:343A.
Levy et al.
The Journal of Pediatrics December 1996
Vitreous hemorrhage as an ophthalmic complication of galactosemia Harvey L. Levy, MD, Anne E. Brown, JD, Steven E. Williams, MD, and Eugene de Juan, Jr., MD From the Division of Genetics, Children's Hospital and the Department of Pediatrics, Harvard Medical School, Boston, Massachusetts; Doherty, Rumble & Butler Professional Association, Attorneys at Law, St. Paul, Minnesota; and The Wilmer Ophthalmological Institute, Johns Hopkins Hospital, Baltimore, Maryland
A major complication of galactosemia is cataracts. This is usually considered to be the sole ophthalmic feature of this disorder. However, we have encountered vitreous hemorrhage, a very rare ophthalmic finding, in five neonates with galactosemia and have found four probable additional cases in the literature. All of these infants had severe neonatal manifestations of galactosemia and were discovered to have vitreous hemorrhage by ophthalmologic examination initiated by the observation of clouding of the eye or on a routine basis. The infants lost most or all vision from the affected eye. Retinal abnormalities were present in the involved eyes of the five neonates of whom we have direct knowledge. Thus we believe that retinal hemorrhage is the most likely source of the vitreous hemorrhage and that the coagulopathy associated with neonatal disease in galactosemia leads to vitreous hemorrhage. Prompt recognition and therapy for the coagulopathy would likely prevent vitreous hemorrhage in galactosemia. (J Pediatr 1996; 129:922-5) Galactosemia is a metabolic disorder caused by a defect in galactose 1-phosphate uridyltransferase, one of three enzymes required to fully metabolize galactose (Figure). It occurs with a frequency of approximately 1:62,000 in the general population. 1 Neonates with this inborn error who breast-feed or are fed a regular infant milk formula accumulate galactose 1-phosphate and galactose from the galactose liberated from milk lactose by intestinal lactase (Figure). The elevated levels of galactose 1-phosphate produce neonatal illness characterized by vomiting, jaundice, fiver dysfunction, weight loss, and "oil droplet" cataract. 2 Prompt withdrawn of milk results in rapid reversal of these features, whereas delay in treatment places the infant at high risk of bacterial sepsis and meningitis with resulting neonatal death or irreversible neurologic disease. 3' 4 Cirrhosis and mental retardation develop in most untreated children with galactosemia who survive the neonatal period, 5 and almost all have cataracts, 6 usually considered to be the sole ophthalmic complication of this disorder. Submitted for publication Feb. 12, 1996; accepted July 3, 1996. Reprint requests: Harvey L. Levy, MD, I.C. Smith 106, Children's Hospital, 300 Longwood Ave., Boston, MA 02115. Copyright © 1996 by Mosby-Year Book, Inc. 0022-3476/96/$5.00 + 0 9/22/?6244
We report vitreous hemorrhage, a rare ophthalmic finding7, 8 in five infants with galactosemia. In addition, we call attention to four probable additional cases from the literature. We believe that vitreous hemorrhage is an ophthalmic complication of galactosemia hitherto unrecognized. CASE REPORTS Patient 1. A 3470 female infant of 40 weeks' gestation was delivered by spontaneous vaginal delivery and had Apgar scores of 9 at 1 minute and 10 at 5 minutes. Physical examination revealed an alert, nonjanndiced infant with equal, reactive pupils, and bilateral red reflexes on ophthalmoscopy. She was discharged home 1 day after birth and received a milk formula after 2 days of breast-feeding. At 9 days of age, the infant was brought to the hospital emergency department. Her weight had decreased to 2900 gm, she had vomiting and diarrhea, her skin was noticeably icteric with redundant skin folds, and she was described as being somnolent. She also had hepatomegaly, elevated total and direct serum bilirubin levels, and abnormal liver function (Table I). Although the infant was noted to have multiple small bruises associated with venous access sites, studies for coagulopathy were not done, and the hematocrit and platelets were normal (Table I). Urinalysis revealed a positive finding for reducing substance. The diagnosis of galactosemia was made, and the infant was admitted for dietary restriction and metabolic support. The admitting physician noted possible corneal clouding of the
The Journal of Pediatrics Volume 129, Number 6
Intestine
Levy et al.
923
Liver
Figure. Liberation of galactose from lactose in the intestine and its metabolism. The enzymes required for galactose metabolism are galactokinase (]), galactose 1-phosphate uridyltransferase (2), and uridine diphosphate-4-epimerase (3). In galactosemia, the defective enzyme is galactose 1-phosphate uridyltransferase.
left eye, and follow-up examination during the hospitalization revealed the infant had a vitreous hemorrhage of the left eye. Three months later she underwent a vitrectomy for a nonclearing vitreous hemorrhage. The intraoperative findings are presented in Table II. The prognosis for vision in the left eye is poor. Patient 2. A 3250 gm boy delivered at 39 weeks of gestation by spontaneous vaginal delivery had Apgar scores of 8 at 1 minute and 9 at 5 minutes. Newborn examinations performed by the pediatrician and nurse indicated normal eyes. Initial feeding included breast milk supplemented by a milk formula. At 9 days of age, the boy was admitted to the neonatal intensive care unit because of poor feeding and poor weight gain. Examination revealed a diminished weight of 2800 gin, jaundice, hepatomegaly, and blood oozing from previous venipuncture sites. Laboratory analysis revealed elevated total and direct serum bilirubin levels, markedly abnormal results of fiver function studies, decreased platelet counts, prolonged prothrombin and partial thromboplastin times, and a low fibrinogen level (Table I). Urinalysis disclosed 4+ reducing substance and absent erythroeyte galactose 1-phosphate uridyltransferase activity. The diagnosis of galactosemia was made, and the patient was given a nonlactose formula. Platelet and fresh frozen plasma transfusions were given to reverse the coagulopathy. Clouding of the right eye was noted at 10 days of age. Ophthalmologic examination revealed reactive pupils and clear lenses but vitreous hemorrhage of the right eye. A vitrectomy of the right eye was performed at 3 weeks of age. The intraoperative examination findings are presented in Table II. Later, at 6 weeks of age, examination with the patient under anesthesia for possible cataract extraction of the right eye revealed severe retinal scarfing with traction elevation in all quadrants. The prognosis for vision in the right eye is poor.
Patient 3. A 1400 gm male infant was delivered by cesarean section at 31 weeks of gestation with Apgar scores of 6 at 1 minute and 9 at 5 minutes. The neonatologist reported the corneas to be clear and the presence of a red reflex bilaterally. A second neonatologist also reported the eyes to be normal. The infant was breastfed. At 9 days of age, his weight had decreased to 1380 gin, he bad jaundice with an enlarged liver, and bruising of the right foot. During the next 3 days, the bilirubin levels increased despite phototherapy (Table I), and cyanosis, temperature instability, lethargy, mad diarrhea developed. At 12 days of age, the blood galactose Levelwas reported as elevated, and a subsequent markedly elevated blood galactose l-phosphate level confirmed the diagnosis of galactosemia. Breast-feeding was discontinued and the infant was fed a nonlactose formula. His condition rapidly hnaproved; he was discharged at 1 month of age. At 5 weeks of age, during a routine examination for retinopathy of prematurity, the infant was noted to have vitreous haze and a diagnosis of vitreous hemorrhage was made. A follow-up examination with the patient under anesthesia was performed at 4 months of age. The results of the examination are presented in Table II. Although he is considered legally blind, this child has some functional vision. This case has been reported in abstract form by Buist et al.9 Patient 4. A 4400 gm male infant was delivered by forcepsassisted vaginal delivery at 41 weeks of gestation; the infant had Apgar scores of 9 at 1 minute and 10 at 5 minutes. Results of ocular examinations on newborn admission and discharge were normal. The infant was breast-fed initially but feeding problems resulted in use of a milk formula. At 10 days of age, a nonlactose formula was started because of continued feeding problems. At 18 days of age, the diagnosis of galactosemia was confirmed by newborn screening and the infant had an ophthalrnologie exam-
924
Levy et al.
The Journal of Pediatrics December 1996
Table I. Laboratory values in the infants with galactosemia and vitreous hemorrhage Age of diagnosis (days) Case
Galactosemia
Vitreous hemorrhage
1 2 3 4 5
9 9 12 10 36
10 10 38 17 58
Prothrombin/partial thromboplastin time (seconds)
Hematocrit (%)/ platelets (in thousands)
Alanine aminotransferase/ aspartate aminotransferase (U/L)
Bilirubin (total/direct) (mg/dl)
Not done 23.4/14.3 Not done Not dont 16.7/117
59.3/210 50.6/38 45.3/385 Not done 30/254
123/129 140/140 Not done Not done 92/196
18.2/3.8 17.2/0.9 11.4/0.7 Not done 24.9/1.1
Table II. Intraoperative ocular findings in galactosemic infants with vitreous hemorrhage Case I (left eye only)
Case 2 (right eye only)
Case 3 (both eyes)
Dense vitreous hemorrage with fibrinous response Markedly sclerotic retinal vessels Thick epiretinal membrane (assumed to be the posterior hyaloid) present over surface of retina Scattered intraretinal punctate deposits Small retinal fold extending along supertemporal and inferotemporal arcades Macula appeared "flat"
Dense tan and red vitreous hemorrhage Dense packing of RBCs on the posterior lens capsule Severe subretinal scarfing in temporal and inferior retina extending to fovea (resolving subretinal hemorrhage) Scarfing and residual subretinal blood in far periphery superiorly and nasally
Right eye (examination with infant under anesthesia) Central serous retinal elevation Macular scarfing Dense midperipheral scarfing Left eye (examination with infant under anesthesia) Dense vitreous stranding Dense vitreous band obscured clear view of macula but no macular scarring noted Dense midperipheral retinal scarring with very dense retinal haze and band formation
Case 4 (right eye only) Dense vitreous hemorrhage (straw-colored "sheets" of RBCs) Posterior hyaloid detached over the retinal pole Nasal portion of retina hemorrhagic
Case 5 (left eye only) Dense vitreous hemorrhage (ochre-colored) Attenuation of retinal arterioles Optic nerve and macula dragged temporally Submacular and temporal subretinal blood Hyperpigmented cells on retinal surface
RBCs, Red blood cells.
ination. This revealed no apparent pupillary defect but mild cataracts of both eyes and no red reflex of the right eye. A diagnosis of probable vitreous hemorrhage was made and observation for clearing of the hemorrhage was planned. However, 6 days later the infant was admitted to the hospital with multifocal septic arthritis and osteomyelitis caused by Escherichia coll. When ultrasonography of the right eye revealed persistent vitreous debris, the diagnosis of endogenous endophthalmitis was considered. Microscopic examination of the vitreous contents revealed many erythrocytes but only rare leukocytes. A vitrectomy in the right eye was performed. The intraoperative findings are presented in Table II. At 14 weeks of age, retinal hyperpigmentation had replaced the hemorrhage. At age 6fi years, the child's visual acuity was 20/50 in both eyes with persistent right esotropia and nystagmus. Patient g. A 3440 gm boy was born by uncomplicated spontaneous vaginal delivery at 38 weeks of gestation. Apgar scores were 7 at 1 minute and 9 at 5 minutes. The neonatal admission and dis-
charge examination noted intact red reflexes bilaterally. The infant was breast-fed. At 5 weeks of age, a physical examination revealed failure to regain birth weight, jaundice, hepatomegaly, prolonged bleeding from venipuncture sites, and bilateral absence of red reflexes. Laboratory studies disclosed hyperbilirubinemia, markedly abnormal liver function test results, and prolonged prothrombin and partial thromboplastin times (Table I). When the urinalysis revealed reducing substance and a galactose level of 900 mg/dl, the diagnosis of galactosemia was made. Ophthalmic evaluation at 5 weeks of age revealed bilateral cataracts. After the infant's medical status was stable, extracapsular cataract extraction of the left eye was performed. Intraoperatively a vitreous hemorrhage was foun& Subsequently vitrectomy for nonclearing vitreous hemorrhage was performed. The intraoperafive findings are presented in Table II. The prognosis for vision in the left eye is poor.
The Journal of Pediatrics Volume 129, Number 6
DISCUSSION This report documents vitreous hemorrhage in five neonates with galactosemia. In addition, we have found four previously re,ported cases of galactosemia in which vitreous hemorrhage was probably also present. 5' 10 Vitreous hemorrhage is rare in neonates and is usually associated with perinatal complications]' 8 Only one of the five infants with galactosemia we describe had perinatal difficulties, indicating that vitreous hemorrhage in these infants was most likely a complication of galactosemia. We believe that hemorrhage from retinal vessels is probably the source of the vitreous blood. The five infants in our case reports had retinal abnormalities ranging from hemorrhages to subretinal scarring, the latter likely associated with a resolving hemorrhage. Although retinal hemorrhage in the neonate is "very frequent, occurring in 25% to 37% of infants born by vaginal delivery, 11-13 the typical neonatal retinal hemorrhage usually resolves by 10 days of age without leaving residual damage. 14 More serious hemorrhage into the vitreous and subretinal space is very rare without other evidence of disease or injury. In the patients with galactosemia whom we describe, the hemorrhages were all severe and did not appear to be related to the typical benign neonatal intraretinal hemorrhage. Although very unlikely, it is possible that hemorrhage from neovascularized areas of the choroid could result in vitreous bleeding. Moreover, retinal vessels overlying the optic disc may hemorrhage through the disc, as can hemorrhages from deep in the parenchyma of the optic nerve. The vitreous hemorrhage in these infants with galactosemia is likely to have resulted from the coagulopathy associated with untreated galactosemia. The two infants in whom coagulation factors were examined had prolonged prothrombin and partial thromboplastin times (Table I). One of these infants (Case 2) also had a reduced fibrinogen level. Braises and prolonged bleeding at venipuncture sites, or both, were noted in two of the other three infants. Korson et al.15 have found that coagulopathy is one of the most frequent early findings in neonates with galactosemia and may be present with otherwise little evidence of liver disease. Supporting the likelihood that coagulopathy in galactosemia is the antecedent to vitreous hemorrhage is the disseminated intravascular coagulopathy in several of the reported cases of infants without galactosemia who sustained vitreous hemorrhage. 7, s Fragility of the retinal vessels in the neonate, perhaps exacerbated by galactosemia, is most likely a major contributing factor to the vitreous hemorrhage in the presence of coagulopathy.
Levy et al.
925
Delay in diagnosis and treatment of galactosemia in the neonate to beyond the first week of life results in substantial coagulopathy.I5 Thus vitreous hemorrhage can probably be largely prevented in this disorder by early diagnosis and withdrawal from milk together with prompt attention to the possibility of coagulopatby and administration of fresh frozen plasma when coagulopathy is detected. We thank the parents who so willingly allowed us to obtain this information. REFERENCES
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