Full text of DOI:10.1007/s12009-000-0072-8

A B S T R A C T
We report an unusual case of acute recurrent bilateral multifocal
choroidal neovascularization that was associated with histological-
ly proven membranoproliferative glomerulonephritis type II and did
not resolve with laser photocoagulation. Early development of sub-
retinal neovascular membranes with widespread retinal pigment
epithelial changes in this condition may herald poor prognosis
despite laser ablation of the neovascular tuft.
C A S E R E P O R T
Occurrence of Atypical Acute Bilateral
Multifocal Choroidal Neovascularization
in Membranoproliferative
Glomerulonephritis Type II
K.V. Chalam, MD, MS, FACS, Junping Li, MD,
PhD, & Ramesh C. Tripathi, MD, PhD, FACS
embranoproliferative glomerulonephritis (MPGN)
is a group of diseases characterized histologically
M
by alterations in the basement membrane and prolifer-
ation of glomerular cells. Based on distinct ultrastruc-
tural and immunofluorescence findings, primary
MPGN can be divided into 2 major types: type I and
type II.1 In type II, MPGN of electron-dense material of
unknown origin is deposited in the glomerular base-
ment membrane proper.1 Ocular histopathologic
changes originally reported in patients with MPGN
type II described dense deposits in the basement mem-
brane of the ciliary epithelium and throughout the
inner collagenous layer of Bruch membrane that simu-
lated drusen.2-4
In patients with a long history of renal disease,
more numerous and larger subretinal nodules as well
as atrophic changes were found.5 Clinical observations
suggest that the occurrence and progression of
retinopathy in these patients is a slow process with
vision usually not affected.5 Thus far, the association
of subretinal neovascular membranes is described in
only 4 cases with a history of renal disease longer than
15 years.6 We report an unusual case of acute bilateral
multifocal choroidal neovascularization in a patient
with type II MPGN that progressed during a period of
3 months to visual loss despite laser therapy.
Reprints:
Ramesh C. Tripathi, MD, PhD, FACS, South Carolina Eye Institute, Four Richland Med-
ical Park, Suite 300, Columbia, SC 29203.
The authors are from the Department of Ophthalmology, University of South Carolina
School of Medicine, Columbia, SC. Dr. Chalam is currently at the University of Florida
College of Medicine, Gainesville, Fla.
Acknowledgments
Financial support was provided by Research to Prevent Blindness, Inc., New York, NY,
and Vision Research Foundation.
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ANN OPHTHALMOL. 2000;32(4):320–324

Materials & Methods
chronic renal failure with nephrotic syndrome
ensued, which necessitated hemodialysis. At that time
serum complement levels (C-3 and C-4) were normal;
however, the patient exhibited persistently elevated
glucose levels despite insulin therapy. He was await-
ing renal transplantation.
Complete eye examinations of the patient included
measurement of visual acuity, pupillary reaction,
Goldmann applanation tonometry and perimetry,
and detailed ophthalmoscopy, as well as fundus pho-
tography and fluorescein and indocyanine-green
angiography.
Ocular examination. The patient had corrected
visual acuity of 20/30-3 in the right eye and 20/40 in
the left eye. On ocular examination, pupils, visual
fields, applanation tonometry, and slit-lamp evalua-
tion of the anterior segment were all unremarkable
and the ocular media were clear. Biomicroscopic
examination of the fundus revealed bilateral, multi-
focal, symmetrical peripapillary subretinal hemor-
rhages (Fig 1). A small subretinal hemorrhage with
serous elevation of the overlying neurosensory retina
was noted immediately above and temporal to both
foveae. A larger area of subretinal hemorrhage was
evident above the right fovea. Biomicroscopic exami-
nation with a contact fundus lens revealed scant, ill-
defined, small yellow deposits at the level of the
retinal pigment epithelium (RPE). There was no evi-
dence of peripapillary chorioretinal scarring or stig-
mata of age-related macular degeneration. The
peripheral retina was unremarkable. Blood pressure
was well controlled with medication.
Fluorescein angiography revealed the presence of a
well-defined juxtafoveal choroidal neovascular mem-
brane measuring about 1000 µm in diameter above the
right fovea (Fig 2A). A larger neovascular membrane
was evident in a symmetrical position in the left eye
(Fig 2B). There were multiple areas of transmitted
hyperfluorescence above and below the left optic nerve
and a small amount of fluorescein leakage temporal to
the right optic nerve. In the right eye, hyperfluores-
cence was partially blocked below the optic nerve that
was thought to represent an additional choroidal neo-
vascular membrane. Indocyanine-green angiography
did not reveal any neovascular activity (Fig 3).
Renal biopsy tissue, fixed in a phosphate-buffered
4% formaldehyde and 1% glutaraldehyde solution,
was divided into 2 pieces. One piece was osmicated,
dehydrated in ascending grades of ethanol, and was
finally embedded in epoxy resin for transmission elec-
tron microscopy. The other piece of tissue, after initial
fixation and alcohol dehydration, was embedded in
paraffin wax. Sections 6 to 8 µm in thickness were cut
from the paraffin block for routine histologic and
immunofluorescence staining.
For immunostaining, deparaffinized and rehydrat-
ed sections were mounted on polylysine coated slides
and incubated with a goat polyclonal antibody against
human complement C3 (1:8 dilution, Sigma, St. Louis,
Mo). Visualization of the primary antibody was per-
formed by using the fluorescein-conjugated rabbit
anti-goat IgG (1:64 dilution, Sigma), and epifluores-
cence microscopy. Replacement of the primary anti-
body with normal nonimmune goat serum served as a
negative control.
Ultrastructural evaluation of the biopsy was carried
out on ultrathin sections stained with uranyl acetate
and lead citrate specimen by using a Hitachi 600 elec-
tron microscope (Tokyo, Japan).
Results
The patient, a 45-year-old white man, had a 2-week
history of rapid deterioration in vision. He had no
prior ocular disease and had an unremarkable family
history. The patient was on hemodialysis for advanced
renal disease and received antihypertensive therapy
with minoxidil and nifedipine for more than 6 months.
Eighteen months earlier, severe systemic hyperten-
sion heralded the onset of acute renal failure. Subse-
quently his renal function did not improve and
The patient underwent argon laser photo ablation
(50–100 µm in size, 0.3–0.4 W, 0.2 sec, 92 spots) of the
left juxtafoveal neovascular membrane; 2 weeks later
A
B
Fig 1.—Fundus photograph of posterior pole showing bilateral peripapillary hemorrhage with subretinal serous fluid above and temporal to both foveae. Ill-defined subretinal yel-
low lesions were seen in right (A) and left (B) eyes on fundus biomicroscopy (arrows).
ANN OPHTHALMOL. 2000;32(4)
321

A
B
Fig 2.—Digital angiogram of (A) early venous phase in the right eye showing well-defined choroidal neovascular membrane, and (B) late venous phase in the left eye with larg-
er, symmetric neovascular membrane. Note also the transmission of hyperfluorescence temporal to and below the right fovea as well as at the temporal edge of the nerve.
A
B
Fig 3.—Late-phase indocyanine-green digital angiogram of (A) left and (B) right eyes.
he complained of decreased vision in the right eye. On
examination, visual acuity was 20/40 in the right eye
and 20/60+2 in the left eye. The neovascular mem-
brane in the right eye had enlarged and was treated
with argon green laser (50–100 µm in size, 0.3–0.4 W, 0.2
sec, 124 spots).
membrane was performed with krypton red laser. Two
weeks later, the patient’s visual acuity had diminished
to 20/400 in the right eye and counting finger in the
left eye. Examination revealed subfoveal neovascular-
ization in the right eye and a disciform scar in the left
fovea.
Two weeks later, visual acuity had decreased to
20/100 in the right eye and 20/400 in the left eye.
Repeat fluorescein angiography at this time demon-
strated recurrent neovascularization in the parafoveal
region of the right eye and early disciform scarring of
the lesion in the left eye with foveal involvement (Fig
4). Repeat focal laser photo ablation (50-100 µm in size,
0.3–0.4 W, 0.2 sec, 144 spots) of the right neovascular
Histopathology and immunofluorescence stain-
ing. Histologic examination of the renal biopsy speci-
men revealed proliferation of mesangial cells,
increased mesangial matrix, and a markedly thickened
basement membrane (Fig 5). The lobular architecture
of the glomerulus was accentuated. Complement C3
immunofluorescence staining demonstrated a positive
reaction product in the peripheral capillary wall and
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ANN OPHTHALMOL. 2000;32(4)

A
B
Fig 4.—Digital fluorescein angiogram showing venous phase of both eyes, with (A) recurrent choroidal neovascular membrane in the right eye and (B) disciform changes in the
left fovea.
Fig 5.—Light micrograph of kidney demonstrating hypercellular, lobulated glomeru-
lus with thickened capillary walls (hematoxylin-eosin, × 850).
Fig 6.—Immunostaining for complement C3 revealing positive staining around
peripheral capillary walls and mesangium (× 700).
mesangium (Fig 6). The negative control did not show
staining of any structure.
Ultrastructurally, an irregular, ribbonlike, electron-
dense, homogeneous structure was observed in the
glomerular basement membrane proper (Fig 7).
Discussion
Choroidal neovascularization in association with renal
disease is an unusual finding.7 Most retinal complica-
tions associated with renal dysfunction involve
microvascular changes of the retinal blood vessels sec-
ondary to the attendant systemic hypertension. Other
vascular causes of acute renal failure, such as periar-
teritis nodosa, Wegener’s granulomatosis, or throm-
botic thrombocytopenic purpura can produce retinal
vasculitis, tortuosity, or thrombosis.7 Changes seen
with hemodialysis are also usually vascular in origin
and include central retinal vein occlusion, cortical
blindness, and anterior ischemic optic neuropathy.8-10
Fig 7.—Transmission electron micrograph of the kidney, showing homogeneous elec-
tron-dense deposits within basement membrane proper (double arrows) (× 54,000).
ANN OPHTHALMOL. 2000;32(4)
323

The pathologic changes revealed by light
microscopy as well as by immunofluorescent staining
of the renal specimen indicate that our patient has
MPGN type II (dense deposit disease). The electron-
dense deposits that were observed within basement
membrane proper further confirm the diagnosis.1
Patients with MPGN type II have been noted to mani-
fest partial lipodystrophy that includes variable glu-
cose intolerance,1 as was found in our patient.
However, our patient did not display low levels of
serum complements as has been described in associa-
tion with some cases of MPGN type II.5
type II. The rapid onset from the time of diagnosis is
unusual, but this appears to correlate with the
advancement of the subretinal neovascularization
despite laser treatment. Our case contrasts with those
patients who had long-standing renal dysfunction
prior to the onset of neovascular complications and,
when treated with laser, responded well.5,6 The scant
amount of clinically detectable dense deposits appears
to conform with the finding of Leys et al,5 who noted
an absence of subretinal nodules in 2 patients early in
the course of their disease. Diffuse RPE changes on
fluorescein angiography documented in the previous
report were also found in our patient.
Patients with MPGN type II are at risk of signifi-
cant complications due to associated retinal pigment
epithelial dysfunction. In addition, the typical oph-
thalmic findings may be helpful in aiding the diagno-
sis of the patient’s underlying renal disorder. The
early development of subretinal neovascular mem-
branes may herald a poor prognosis despite laser
treatment.
Previously, Leys et al5,6 described a series of
patients with chronic MPGN type II who developed
subretinal neovascular membranes in the course of
the illness. Their 4 patients, who had biopsy-proven
MPGN type II, had fundus findings similar to each
other that consisted of extensive pigment epithelial
abnormalities and a varying number of small drusen-
like subretinal deposits. In addition, 3 of the 4 patients
demonstrated alterations of the electro-oculogram
with reduced Arden ratios between 150% and 160%
(light-peak to dark-trough ratio). Pigment epithelial
disease is not reported in any other glomerulopathies
or in MPGN type I.2,11 The ocular histopathologic find-
ings in association with MPGN type II include elec-
tron-dense deposits in the inner collagenous layer of
Bruch membrane, which resemble deposits found in
the glomerular basement membrane.3,4
References
1. Glassock RJ, Adler SG, Ward HJ. Primary glomerular diseases. In:
Brenner BM, ed. The Kidney. 5th ed. Vol II. Philadelphia: Saun-
ders; 1996:1392–1497.
2. Duvall-Young J, Short C D, Raines M F, Gokal R, Lawler W. Fundus
changes in mesangiocapillary glomerulonephritis type II: clinical
and fluorescein angiographic findings. Br J Ophthalmol. 1989;73:
900–906.
3. Duvall-Young J. Letter to the editor. Br J Ophthalmol. 1989;73:932–
938.
A recent report of central serous retinopathy in
MPGN type II confirms the propensity of such
patients to develop disease related to dysfunction of
the RPE and Bruch membrane.12 Unusual causes of
choroidal neovascularization not associated with age-
related macular degenerative changes include acute
multifocal posterior placoid pigment epitheliopathy,
rubella retinopathy, chorioretinal folds, photocoagula-
tion, chronic papilledema, and hyaline bodies of the
optic nerve.13 Idiopathic choroidal neovascularization
of the macula has been ascribed to a forme fruste of
the ocular histoplasmosis syndrome when seen in
young patients. However, the visual prognosis in
patients with idiopathic choroidal neovascularization
is usually good.13 The rare and ill-defined condition
known as the pseudo-inflammatory macular dystro-
phy of Sorsby14 has an autosomal dominant mode of
inheritance and is manifested by hemorrhagic, rapid-
ly progressive disciform lesions of the macula, fol-
lowed by pigmentary changes in the peripheral retina.
Our patient suffered from chronic renal failure and
developed rapidly progressive and destructive, sym-
metrical choroidal neovascular membranes in associa-
tion with diffuse, scattered RPE changes. The
widespread and aggressive nature of the ocular dis-
ease in a relatively young person indicates a global
defect in the RPE or its subjacent structures.
4. Duvall-Young J, MacDonald M, McKechnie N. Fundus changes in
(type II) mesangiocapillary glomerulonephritis simulating
drusen: a histopathological report. Br J Ophthalmol. 1989;73:297–
302.
5. Leys A, Vanrenterghem Y, VanDamme B, Snyers B, Pirson Y, Leys
M. Fundus changes in membranoproliferative glomerulonephritis
type II: a fluorescein angiographic study of 23 patients. Graefes
Arch Clin Exp Ophthalmol. 1991;229:406–410.
6. Leys A, Michielsen, Leys M, Vanrenterghem Y, Missoten L, Van-
Damme B. Subretinal neovascular membranes associated with
chronic membranoproliferative glomerulonephritis type II. Grae-
fes Arch Clin Exp Ophthalmol. 1990;228:499–504.
7. Howes Jr. EL. Renal failure, dialysis and transplantation. In: Gold
DH, Weingeist TA, eds. The Eye in Systemic Disease. Philadelphia:
JB Lippincott Company; 1990:507–509.
8. Barton CH, Vaziru ND. Central retinal vein occlusion associated
with hemodialysis. Am J Med Sci. 1979;277:39–47.
9. Moel DI, Kwyn YA. Cortical blindness as
a complication of
hemodialysis. J Pediatr. 1978;93:890–891.
10. Servilla KS, Groggel GC. Anterior ischemic optic neuropathy as a
complication of hemodialysis. Am J Kidney Dis. 1986;8:61–63.
11. Michielsen B, Leys A, VanDamme B, Missoten L. Fundus changes
in chronic membranoproliferative glomerulonephritis type II. Doc
Ophthalmol. 1991;76:219–229.
12. Ulbic MRW, Riordan-Eva P, Holz FG, Rees HC, Hamilton AM.
Membranoproliferative glomerulonephritis type II associated
with central serous retinopathy. Am J Ophthalmol. 1993;116:410–
413.
13. Gass JDM. Specific choroidal diseases causing macular detach-
ment. In: Gass JDM, ed. Stereoscopic Atlas of Macular Diseases.
St. Louis, Mo: CV Mosby Co; 1987:198–201.
14. Deutman AP. Macular dystrophies. In: Ryan SJ, Schachat AP,
Murphy RP, Patz A, eds. Retina. St. Louis, Mo: CV Mosby Co; 1989:
281–283.
We believe that our patient represents an atypical
form of choroidal neovascularization due to MPGN
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