Volume 19 Number 1 / February 2015
Alexander and Miller
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A case of frosted branch angiitis in an immunocompromised child Janet Leath Alexander, MD,a,b and Marijean Miller, MDb Frosted branch angiitis is a rare vascular reaction believed to be a nonspecific immune response to an infective, neoplastic, or idiopathic insult. The clinical presentation is characteristic and typically affects children and younger adults, and the prognosis is good. We report a case of frosted branch angiitis during immune recovery in a 2-year-old boy with Langerhans cell histiocytosis on systemic immunosuppressive therapy.
Case Report
A
previously healthy 2-year-old boy was diagnosed and treated at Children’s National Medical Center in Washington, DC, for multisystem Langerhan’s cell histiocytosis (LCH) after 8 months of fevers and lethargy. His initial treatment with vinblastine and prednisone failed to induce remission, and therapy was changed to clofarabine treatment 3 months after his initial diagnosis. After 1 month of clofarabine, treatment was held for cell count recovery due to absolute neutrophil count (ANC) of \1 and frequent neuropenic fevers. He was treated empirically for infection with meropenem and amphotericin and was receiving supportive weekly transfusions of red blood and platelets. He was also on filgrastim for low ANC. At this time in clinical course, ophthalmology was consulted for fungemia evaluation based on positive betaglycan fungal marker in serum but no positive cultures. On examination, visual acuity was central, steady, and maintained in each eye, with no preference for either eye. Fundus examination was significant for small elevated clusters of white specks in the peripheral retina of both eyes (Figure 1). There was no vitritis or uveitis, and our suspicion for fungal etiology was low based on appearance. The white specks were observed by dilated fundus examination every few days for 2 weeks, at which time a sudden change was noted, including a new crop of white specks near vascular inflammation, with associated sheathing, and retinal edema (Figure 2). At the time of the sudden retinal changes, the patient’s systemic condition
Author affiliations: aUniversity of Maryland, Baltimore, Maryland; bChildren’s National Medical Center, Washington, DC Submitted May 18, 2014. Revision accepted August 30, 2014. Correspondence: Janet Leath Alexander, MD, Department of Ophthalmology and Visual Sciences, University of Maryland, 419 WestRedwood Street, Suite 479, Baltimore, MD 21201 (email: [email protected]). J AAPOS 2015;19:75-76. Copyright Ó 2015 by the American Association for Pediatric Ophthalmology and Strabismus. 1091-8531/$36.00 http://dx.doi.org/10.1016/j.jaapos.2014.08.014
Journal of AAPOS
FIG 1. Fundus photograph 2 weeks prior to development of frosted branch angiitis demonstrating small clusters of white specks (black arrow) with otherwise normal retinal appearance.
FIG 2. Fundus photo 1 day prior to development of fulminant frosted branch angiitis demonstrating an increased number of white specks (circled) with early retinal vessel changes.
had dramatically changed for the better. He was able to be extubated and became eligible for transfer out of the intensive care unit where he had been for the previous 2 months. His ANC increased from a range of 0-1 to 500 and the next day continued to climb to 650. While his systemic condition improved over the subsequent days, his retinal vasculitis worsened (Figure 3). The patient remained asymptomatic and denied eye pain but was observed to have decreased vision in the more affected left eye based on strong preference for the right eye. At the onset of the frosted branch appearance to his retinal vessels, empiric antiviral therapy was initiated and infection workup was repeated. The workup included herpes simplex virus, varicella-zoster virus, cytomegalovirus (CMV), Epstein-Barr virus, rubella, tuberculosis, syphilis, and toxoplasmosis, all of which were negative. Of note, during treatment with antiviral empiric therapy, while awaiting results of infectious workup, there was no improvement and mild worsening of the vasculitis. When
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Alexander and Miller
FIG 3. Fundus photograph 1 month after the first white specks were noted in the retina showing frosted branch angiitis of the left eye. A, Posterior pole. B, Periphery with frosted branch appearance of vessels and persistence of scattered focal white specks, similar to those noted prior to the development of frosted branch vessel appearance.
infectious etiology had been ruled out, 21 days after the first white spots, systemic treatment of presumed primary frosted branch angiitis with intravenous methylprednisolone was initiated at a dose of 1 mg/kg every 12 hours for 10 days, and fundus examination was followed closely for the first 3 days and then every other day until definitive improvement was observed. After the 10 days of treatment, the retinal appearance had nearly normalized and remained stable over 6 months of follow-up after treatment.
Discussion The first case of frosted branch angiitis (FBA) in a child was reported in 1976, and although additional case reports have since been published, it remains a rare and nonspecific finding. Primary FBA, a diagnosis of exclusion, is responsive to steroid therapy and has a good prognosis. Complications can occur, including macular edema, macular scarring, neovascularization, and retinal detachment. FBA is generally bilateral, and can be asymmetric, as in the present case. This case presents several novel features. First, it demonstrates the fundus appearance just prior to development of
Volume 19 Number 1 / February 2015 FBA. This is also one of the youngest patients described and is also one of the few African American patients described in the literature.1,2 This is also the first case of FBA in a child with LCH and the first case of presumed immune reconstitution FBA. Based on the timing of this patient’s retinal vasculitis and on the exclusion of infectious etiology, the diagnosis of immune reconstitution FBA was made. There was a notable absence of vitritis and uveitis making this particular presentation of immune reconstitution FBA unique. The diagnosis was further confirmed by observation of excellent response to systemic steroids. Recently Leeamornsiri and colleagues3 reported a case of immune reconstitution uveitis in an adult patient with CMV,3 which can be associated with FBA. Serology was negative for CMV in our case. In the present case there is no known association between LCH and FBA, which occurred when the patient was actively recovering immune system function after 3 months of chemotherapy and immunosuppression. Immune reconstitution syndrome or immune reconstitution inflammatory syndrome occurs when a patient exhibits a paradoxical deterioration in a particular aspect of clinical status despite improvement in overall lymphocyte counts. This phenomenon is most commonly associated with immune recovery in immunosuppressed HIV patients when they begin highly active antiretroviral therapy (HAART). This deterioration is a result of an exuberant inflammatory response toward unknown antigens. The syndrome can lead to a variety of clinical signs, including lymphadenitis, pneumonitis, meningitis, and uveitis. The treatment for these patients is to continue HAART and combine it with a short-term course of systemic anti-inflammatory agent.
Literature Search MEDLINE, MEDLINE in process, Cochrane library, Scopus, and Scholar were searched without language or date restriction on February 1, 2014, using the term frosted branch angiitis and each of the following: retina, pediatric, childhood, infancy, Langerhan’s cell histiocytosis, immune reconstitution, and immunocompromise.
Acknowledgments The authors thank Ms. Carmelina Trimboli-Heidler for her expert photography. Thanks also to Drs. Reginald Sanders, Michael Lai, and Aziz Khanifar for their retinal consultation and advice in this case. References 1. Haque MN, Basu S, Padhi TR, Kesarwani S. Acute idiopathic frosted branch angiitis in an 11-month-old infant treated with intravitreal triamcinolone acetonide. J AAPOS 2012;16:487-8. 2. Taban M, Sears JE, Crouch E, Schachat AP, Traboulsi EI. Acute idiopathic frosted branch angiitis. J AAPOS 2007;11:286-7. 3. Leeamornsiri S, Choopong P, Tesavibul N. Frosted branch angiitis as a result of immune recovery uveitis in a patient with cytomegalovirus retinitis. J Ophthalmic Inflamm Infect 2013;3:52.
Journal of AAPOS
Alexander and Miller
75
A case of frosted branch angiitis in an immunocompromised child Janet Leath Alexander, MD,a,b and Marijean Miller, MDb Frosted branch angiitis is a rare vascular reaction believed to be a nonspecific immune response to an infective, neoplastic, or idiopathic insult. The clinical presentation is characteristic and typically affects children and younger adults, and the prognosis is good. We report a case of frosted branch angiitis during immune recovery in a 2-year-old boy with Langerhans cell histiocytosis on systemic immunosuppressive therapy.
Case Report
A
previously healthy 2-year-old boy was diagnosed and treated at Children’s National Medical Center in Washington, DC, for multisystem Langerhan’s cell histiocytosis (LCH) after 8 months of fevers and lethargy. His initial treatment with vinblastine and prednisone failed to induce remission, and therapy was changed to clofarabine treatment 3 months after his initial diagnosis. After 1 month of clofarabine, treatment was held for cell count recovery due to absolute neutrophil count (ANC) of \1 and frequent neuropenic fevers. He was treated empirically for infection with meropenem and amphotericin and was receiving supportive weekly transfusions of red blood and platelets. He was also on filgrastim for low ANC. At this time in clinical course, ophthalmology was consulted for fungemia evaluation based on positive betaglycan fungal marker in serum but no positive cultures. On examination, visual acuity was central, steady, and maintained in each eye, with no preference for either eye. Fundus examination was significant for small elevated clusters of white specks in the peripheral retina of both eyes (Figure 1). There was no vitritis or uveitis, and our suspicion for fungal etiology was low based on appearance. The white specks were observed by dilated fundus examination every few days for 2 weeks, at which time a sudden change was noted, including a new crop of white specks near vascular inflammation, with associated sheathing, and retinal edema (Figure 2). At the time of the sudden retinal changes, the patient’s systemic condition
Author affiliations: aUniversity of Maryland, Baltimore, Maryland; bChildren’s National Medical Center, Washington, DC Submitted May 18, 2014. Revision accepted August 30, 2014. Correspondence: Janet Leath Alexander, MD, Department of Ophthalmology and Visual Sciences, University of Maryland, 419 WestRedwood Street, Suite 479, Baltimore, MD 21201 (email: [email protected]). J AAPOS 2015;19:75-76. Copyright Ó 2015 by the American Association for Pediatric Ophthalmology and Strabismus. 1091-8531/$36.00 http://dx.doi.org/10.1016/j.jaapos.2014.08.014
Journal of AAPOS
FIG 1. Fundus photograph 2 weeks prior to development of frosted branch angiitis demonstrating small clusters of white specks (black arrow) with otherwise normal retinal appearance.
FIG 2. Fundus photo 1 day prior to development of fulminant frosted branch angiitis demonstrating an increased number of white specks (circled) with early retinal vessel changes.
had dramatically changed for the better. He was able to be extubated and became eligible for transfer out of the intensive care unit where he had been for the previous 2 months. His ANC increased from a range of 0-1 to 500 and the next day continued to climb to 650. While his systemic condition improved over the subsequent days, his retinal vasculitis worsened (Figure 3). The patient remained asymptomatic and denied eye pain but was observed to have decreased vision in the more affected left eye based on strong preference for the right eye. At the onset of the frosted branch appearance to his retinal vessels, empiric antiviral therapy was initiated and infection workup was repeated. The workup included herpes simplex virus, varicella-zoster virus, cytomegalovirus (CMV), Epstein-Barr virus, rubella, tuberculosis, syphilis, and toxoplasmosis, all of which were negative. Of note, during treatment with antiviral empiric therapy, while awaiting results of infectious workup, there was no improvement and mild worsening of the vasculitis. When
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Alexander and Miller
FIG 3. Fundus photograph 1 month after the first white specks were noted in the retina showing frosted branch angiitis of the left eye. A, Posterior pole. B, Periphery with frosted branch appearance of vessels and persistence of scattered focal white specks, similar to those noted prior to the development of frosted branch vessel appearance.
infectious etiology had been ruled out, 21 days after the first white spots, systemic treatment of presumed primary frosted branch angiitis with intravenous methylprednisolone was initiated at a dose of 1 mg/kg every 12 hours for 10 days, and fundus examination was followed closely for the first 3 days and then every other day until definitive improvement was observed. After the 10 days of treatment, the retinal appearance had nearly normalized and remained stable over 6 months of follow-up after treatment.
Discussion The first case of frosted branch angiitis (FBA) in a child was reported in 1976, and although additional case reports have since been published, it remains a rare and nonspecific finding. Primary FBA, a diagnosis of exclusion, is responsive to steroid therapy and has a good prognosis. Complications can occur, including macular edema, macular scarring, neovascularization, and retinal detachment. FBA is generally bilateral, and can be asymmetric, as in the present case. This case presents several novel features. First, it demonstrates the fundus appearance just prior to development of
Volume 19 Number 1 / February 2015 FBA. This is also one of the youngest patients described and is also one of the few African American patients described in the literature.1,2 This is also the first case of FBA in a child with LCH and the first case of presumed immune reconstitution FBA. Based on the timing of this patient’s retinal vasculitis and on the exclusion of infectious etiology, the diagnosis of immune reconstitution FBA was made. There was a notable absence of vitritis and uveitis making this particular presentation of immune reconstitution FBA unique. The diagnosis was further confirmed by observation of excellent response to systemic steroids. Recently Leeamornsiri and colleagues3 reported a case of immune reconstitution uveitis in an adult patient with CMV,3 which can be associated with FBA. Serology was negative for CMV in our case. In the present case there is no known association between LCH and FBA, which occurred when the patient was actively recovering immune system function after 3 months of chemotherapy and immunosuppression. Immune reconstitution syndrome or immune reconstitution inflammatory syndrome occurs when a patient exhibits a paradoxical deterioration in a particular aspect of clinical status despite improvement in overall lymphocyte counts. This phenomenon is most commonly associated with immune recovery in immunosuppressed HIV patients when they begin highly active antiretroviral therapy (HAART). This deterioration is a result of an exuberant inflammatory response toward unknown antigens. The syndrome can lead to a variety of clinical signs, including lymphadenitis, pneumonitis, meningitis, and uveitis. The treatment for these patients is to continue HAART and combine it with a short-term course of systemic anti-inflammatory agent.
Literature Search MEDLINE, MEDLINE in process, Cochrane library, Scopus, and Scholar were searched without language or date restriction on February 1, 2014, using the term frosted branch angiitis and each of the following: retina, pediatric, childhood, infancy, Langerhan’s cell histiocytosis, immune reconstitution, and immunocompromise.
Acknowledgments The authors thank Ms. Carmelina Trimboli-Heidler for her expert photography. Thanks also to Drs. Reginald Sanders, Michael Lai, and Aziz Khanifar for their retinal consultation and advice in this case. References 1. Haque MN, Basu S, Padhi TR, Kesarwani S. Acute idiopathic frosted branch angiitis in an 11-month-old infant treated with intravitreal triamcinolone acetonide. J AAPOS 2012;16:487-8. 2. Taban M, Sears JE, Crouch E, Schachat AP, Traboulsi EI. Acute idiopathic frosted branch angiitis. J AAPOS 2007;11:286-7. 3. Leeamornsiri S, Choopong P, Tesavibul N. Frosted branch angiitis as a result of immune recovery uveitis in a patient with cytomegalovirus retinitis. J Ophthalmic Inflamm Infect 2013;3:52.
Journal of AAPOS
