History of present illness
We present a case of a 77-year-old man referred for evaluation of nonresolving submacular fluid after 18 months of frequent anti–vascular endothelial growth factor (VEGF) injections (aflibercept and ranibizumab) for presumed exudative age-related macular degeneration (AMD). The past ocular history was notable for a diagnosis of possible idiopathic central serous chorioretinopathy (ICSC) 10 years earlier, with associated retinal pigment epithelium (RPE) changes but normal visual acuity. He had undergone bilateral photodynamic therapy (PDT) without resolution of the macular fluid. His chief report was persistently blurred vision with metamorphopsia in both eyes unresponsive to PDT and anti-VEGF therapy.
His past medical history was significant for a diagnosis of monoclonal gammopathy of undetermined significance (MGUS).
Ocular examination findings
The best corrected visual acuities were 20/50 in the right eye and 20/63 in the left eye. Intraocular pressures were normal. Anterior segment examination was unremarkable, including clear corneas with no crystalline deposits. Dilated fundus examination was notable for RPE atrophy inferonasal to the fovea in the right eye and submacular fluid with scattered subretinal vitelliform deposits and mild choroidal folds in both eyes ( Fig. 26.1 A and B). There were no typical or basal laminar drusen in either eye.
Imaging
Optical coherence tomography (OCT) imaging of the right eye showed RPE atrophy, a thick choroid, and a macular neurosensory retinal detachment with mild intraretinal fluid ( Fig. 26.1 C). OCT imaging of the left eye demonstrated a thick choroid and submacular fluid ( Fig. 26.1 D). Fundus autofluorescence (FAF) photography showed scattered hyperautofluorescence corresponding to subretinal vitelliform material, most prominent inferiorly in the left eye ( Fig. 26.1 E and F). Fluorescein angiography (FA) revealed scattered transmission defects in each eye with mild late staining but without definite leakage in either eye ( Fig. 26.1 G and H). Of particular note was the absence of evidence for choroidal neovascularization in either eye by any imaging modality.
Questions to ask
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Does the patient have a history of steroid use? ICSC should be high on the differential diagnosis of treatment-resistant submacular fluid, particularly in a patient with RPE atrophy.
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The patient denied any history of previous or current steroid use.
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What medications does the patient take? Medications such as mitogen-activated protein kinase (MEK) inhibitors can cause subretinal fluid.
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The patient denied use of MEK inhibitors.
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Is there a history of uncontrolled hypertension? Hypertensive choroidopathy can result in serous macular detachments.
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The patient did not have untreated hypertension.
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Does the patient have a family history of AMD, basal laminar drusen, pattern macular dystrophy, or polypoidal choroidal vasculopathy (PCV)? These are common causes of submacular fluid.
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The patient denied a family history of these conditions, and his examination and imaging findings were not suggestive of these diagnoses.
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Is there a history of bone pain, neurological symptoms, or symptoms related to anemia? These symptoms can be seen with multiple myeloma, Waldenström macroglobulinemia, and primary amyloidosis, which are rare causes of treatment-resistant neurosensory macular detachment typically associated with clinical signs of hyperviscosity retinopathy.
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No. However, the patient did have a diagnosis of MGUS and was being monitored by his hematologist.
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Is there any previous diagnosis of an optic pit? Cavitary optic disc anomalies such as optic disc pit and coloboma can result in treatment-resistant neurosensory macular detachment.
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The patient had no history of cavitary optic disc anomalies and no evidence for these on examination.
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Assessment
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This is a case of a 77-year-old man with a past ocular history of possible ICSC presenting with bilateral, treatment-resistant, and angiographically silent macular detachment.
Differential diagnosis
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ICSC
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Exudative AMD
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PCV
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Vitelliform macular detachment associated with basal laminar drusen
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Adult vitelliform pattern dystrophy
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Immunogammopathy maculopathy or monoclonal gammopathy of macular significance (MGMS)
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Optic pit maculopathy
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Hypertensive choroidopathy
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Medication-associated subretinal fluid (e.g., MEK inhibitor maculopathy)
Working diagnosis
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MGMS
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MGMS has recently been described in patients with MGUS. These patients present with submacular fluid and variable subretinal vitelliform material without signs of hyperviscosity retinopathy. The findings may be bilateral or unilateral. ,
Multimodal testing and results
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Fundus photos
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On fundus examination, the patient will typically not demonstrate signs of hyperviscosity retinopathy. By definition, MGUS does not achieve sufficiently high serum protein levels to cause hyperviscosity. Hyperviscosity retinopathy, including dilated, tortuous vessels and retinal hemorrhages, is typically seen if the disease transforms to a malignant condition such as multiple myeloma or Waldenström macroglobulinemia.
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OCT
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As mentioned, our patient’s OCT showed bilateral choroidal thickening with neurosensory macular detachment.
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Treatment-resistant macular detachment with variable accumulation of vitelliform material is the classic finding seen in MGMS.
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FA
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FA in both eyes was notable for the lack of leakage.
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MGMS is characterized by angiographically silent macular neurosensory detachments. These detachments are hypothesized to be due to a transudative process driven by higher-than-normal circulating levels of protein in the serum.
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FAF
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As in our patient, FAF shows variable hyperautofluorescence corresponding to subretinal vitelliform accumulations. ,
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Laboratory testing
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Idiopathic and refractory neurosensory macular detachment may be a sign of underlying malignancy or indicate a premalignant condition. Total serum protein and serum protein electrophoresis should be obtained in such patients.
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Management
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This patient underwent malignant transformation to immunoglobulin (Ig)G-κ lymphoplasmacytic lymphoma, an IgG variant of Waldenström macroglobulinemia. He was treated with Bruton tyrosine kinase (BTK) inhibitor, with gradual resolution of submacular fluid and reduction in choroidal thickening ( Fig. 26.1 I and J). Trace submacular fluid recurred when the BTK inhibitor dose was reduced but remained stable through 6 months of follow-up.
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General management for MGMS is observation with close follow-up by hematology/oncology specialists. Systemic therapy is indicated in the event of malignant transformation, and this frequently results in resolution of submacular fluid.
Follow-up care
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There are no previously established guidelines for follow-up, but we have followed our patients every 3 to 6 months with dilated fundus examination and imaging.
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If the patient demonstrates progression on OCT, more frequent follow-up may be indicated.
Algorithm 26.1 : Algorithm representing macular subretinal fluid in eyes without inflammation
