Multifocal visual evoked
potential (mVEP) results in glaucoma patients correlating very well with
conventional automated perimetry findings. It may indeed be a
viable reality as a clinical diagnostic tool (Graham
et al. ).
New ultrahigh resolution images
for optical coherence tomography (OCT) showed differentiation
of various layers of the retina (including the nerve fiber layer). This approach appears to have
great promise for noninvasively monitoring retinal nerve fiber
layer thickness (Drexler et al.)
The mini symposium entitled
The Structure and Function of Retinal Ganglion Cells in Health and
Disease was an excellent collection of papers that included the properties of
retinal ganglion cells, glial cells, photoreceptor effects in
glaucoma, higher visual centers and their relationship to retinal
ganglion cell input, and several related topics.
Two other mini symposia provided information showing
that there is more processing of visual information in the
outer plexiform layer and bipolar cells than was previously
believed. These findings have significant implications for the input
to retinal ganglion cells.
The large number of presentations on Frequency
Doubling Technology (FDT) with favorable results showed that it
has gained wide acceptance and has value as a clinical
diagnostic tool.
Individual corneal birefringence measures should improve
the diagnostic utility of scanning laser polarimetry by applying
a more appropriate corneal compensation factor for
individual eyes.
New, novel neural network approaches have been applied
for distinguishing glaucomatous visual field loss and for
determining glaucomatous damage to the optic nerve head, and
have yielded performance characteristics (sensitivity, specificity,
area under the ROC curve) that are considerably better than
previous attempts.
Glaucoma patients had an increase in plasma
endothelin-1 levels following a cold provocative test, whereas normal
controls and subjects with Raynaud's syndrome did not. This suggests that some glaucoma patients may have
vascular endothelium dysfunction that leads to exaggerated
endothelin-1 release and subsequent reduction in ocular blood flow (Nicolela et al.).
A third generation optical
coherence tomography system has been developed which has a 3-µm
resolution, which holds promise as a means of objectively monitoring the nerve
fiber layer in glaucoma (Drexler et al.).
[See also Nature Medicine 2001;7:502-7, for great pictures.]
Using a portion of the Advanced
Glaucoma Intervention Study visual field data (7-11-year follow-up),
progression was called in 49% by pointwise linear regression
analysis, 44% by neural network analysis, 43% by clinical
consensus, and only 32% by the AGIS criteria, with the best
agreement (kappa 0.59) for clinical assessment and pointwise linear
regression (Hoffman et al.).
A neutralizing
anti-TGFB2 human monoclonal antibody
has passed safety testing and has yielded an encouragingly
better outcome than placebo (mean IOP 14.5 versus 17.8 mmHg
for placebo, p = 0.12; 13% back on medication versus 38%,
p = 0.29), though a much larger efficacy trial will be
needed (Siriwardena et al.).
Cultured human nerve head astrocytes at 60 mmHg, but
not at ambient pressure, produced nitric oxide synthase type
2, unless inhibited by SN50, an NF-kB inhibitor (Liu and Neufeld).
Measuring and compensating for corneal birefringence
anomalies improves the performance of the Nerve Fiber Analyzer (GDX) in discriminating glaucomatous from normal eyes
(Greenfield et al.).
A device that measures multichannel visual evoked
potentials with occipital cross electrodes while stimulating 58 points
in the visual field achieved good correlation with Humphrey
Visual Field results (Graham et al.).
A randomized trial of SKT versus ALT showed equal
efficacy at 12 months (-6.39 versus -6.03 mmHg), and a trend
towards better results in the subset in whom ALT had been
performed previously (Hodge et al.).
IOP was measured before, and one month and one year
after LASIK by three tonometers and the change in measured
IOP (means: -2.3 by Goldmann; -3.4 by Tonopen; -5.1 by
non-contact) compared to the change in corneal thickness
measured by ultrasound (mean 52 Fm), with the authors
concluding that the change in IOP is too poorly correlated with
the change in corneal thickness to be useful in estimating
the 'true' IOP after LASIK (Shinzato et al.).
The authors found that cannabinoid-specific agonists bound
to receptors in the cytosol, but not cell membranes, of
human ciliary body epithelium and trabecular meshwork cells in
culture, and stimulated GTP binding (Stamer et
al.).
In a randomized trial 52 eyes, each were randomized to
deep sclerectomy with and without a collagen implant, and the
four-year IOPs favored those with the implant (12.7 versus 14
mmHg), as did the percentage of patients at IOP < 21 mmHg
off medication (35% versus 63%) (Shaarawy et
al.).
As always, the New Ideas in Glaucoma session on Tuesday morning served
as a platform for a variety of innovative and thought-provoking papers.
Investigation of mitochondrial gene mutations in glaucoma RM Andrews, PG Griffiths, N Howell, DM Turnbull
Neuro-ophthalmology, Royal Victoria Infirmary, Newcastle, Tyne and Wear, England, Dept of Radiobiology, Galveston, Texas USA.
A family history of glaucoma is present in anywhere between about 15% and 50% of
patients with the most common glaucomas - POAG, juvenile
POAG, pigmentary glaucoma, and exfoliative glaucoma. However, the
relative risk of maternal transmission is six to eight times greater than paternal transmission. It is difficult to explain this difference
in strict Mendelian terms. Mitochondrial DNA is however maternally inherited,
suggesting that mitochondrial gene mutations, which have been described in approximately 100 disorders,
including sensorineural
hearing loss and Leber's optic atrophy, may be a risk factor in glaucoma. Andrews et al undertook whole mitochondrial genome sequencing
in 18 families with evidence of maternally inherited normal-tension glaucoma and 16 control families.
Whole genome sequence data was used
to classify each mtDNA according to haplogroup. Their results suggested that any haplogroup differences detected arose by chance and that
the
mode of apparent maternal inheritance remains to be explained. Genomic imprinting
and trinucleotide repeates remain to be examined, and there
is a need to differentiate between glaucoma and the various disorders and risk factors leading to it.
Correction for CPA Improves SLP Discriminating Power Greenfield DS, Knighton RW, Feuer W, Schiffman J, Zangwill L, Weinreb RN
Bascom Palmer Eye Institute, Univ Miami Sch Med; Glaucoma Center, Univ California at San Diego.
Scanning laser polarimetry (SLP, GDx) provides highly reproducible, quantitative
assessments of the peripapillary retinal nerve fiber layer
(RNFL) using a polarized diode laser light source (780 nm). Since the RNFL is not the only ocular birefringent structure, the
GDx
incorporates an anterior segment compensator device designed to neutralize the
polarization effects of the cornea and lens. Both the
axis and the amount of birefringence are important. The compensator is limited by the assumption that all patients have a fixed
slow axis of
birefringence (corneal polarization axis, or CPA) of 15 degrees nasally downward and a fixed
magnitude of birefringence of 60 nm. Actually, the normal CPA ranges from 90 degrees downward to 54 degrees upward and the
magnitude ranges from 0 to 190 nm. Greenfield et al investigated whether correction for CPA could improve the
diagnostic precision of
SLP for detection of mild to moderate glaucoma. The authors constructed a non-invasive slit-lamp mounted device incorporating two crossed
linear polarizers and an optical retarder in order to measure the slow axis of corneal polarization.
One eye of each of 53
normals and 33 glaucoma patients were evaluated. Logistic regression analysis was
performed and receiver operator characteristic (ROC) curves calculated for 14 retardation parameters. Correction for CPA
significantly improved the discriminating power and area under the ROC curve for 5 of
14 summary retardation parameters (average thickness, ellipse average, inferior average, superior average, andtotal integral). Correction for
CPA significantly (p<<0.001) increased the correlation between visual
function (as measured by corrected pattern standard deviation) and each of
these parameters. The authors concluded that correction for CPA
narrows the distribution of normative RNFL data, increases the correlation between structural damage and visual
function, and
significantly improves the diagnostic precision of SLP.
A new method of multifocal objective VEP perimetry for glaucoma detection. SL Graham, AI Klistorner, I Goldberg, FC Billson
Sydney University, Sydney, NSW, Australia.
Patients who enjoy taking visual field tests are few and far between. An accurate objective
test would not only make patients happy, but
would eliminate ambiguity of interpretation due to fluctuation and error. Graham et al tested the ability of multi-focal pattern visually
evoked potential (ObjectiVision System) to detect glaucomatous visual field defects. The testing
device provided different random patterns to
each of 58 points extending out to 32 degrees nasally. The authors examined 100 patients with high- and normal-tension glaucoma who
had
reproducible Humphrey visual field defects and glaucomatous disc damage and
compared to a data base of 100 normals. The Humphrey field defects
were demonstrated by VEP amplitude reductions in 95 of100 glaucomatous eyes. Two more were identified on
asymmetry analysis, providing a 97%
sensitivity. Asymmetry was very useful early in thedisease looking for signs of damage. A
normal visual field was present in the second eye of 37 patients, while in 22 of these, multifocal objective perimetry showed a defect. Of
these 22, 19 also had a suspicious disc. The
authors concluded that multifocal VEP is capable of detecting change prior to visual field testing, but that limitations in the testing
conditions still need to be overcome.
Photodynamic modulation of wound healing in glaucoma filtration
surgery M Diestelhorst, S Grisanti
University of Cologne, Germany.
Complications of filtration surgery performed with 5-fluorouracil and
mitomycin-C, particularly late bleb leaks, hypotony, and bleb infection, have prompted numerous
investigations into alternative
modalities for the modulation of wound healing. Diestelhorst and Grisanti studied the safety and efficacy of photodynamic therapy (PDT)
using a carboxy-fluorescein derivative (BCECF-AM), a cell-membrane permeable dye absorbed at
the target tissue, to control postoperative
fibrosis after glaucoma surgery in an open-label study in eyes with finger counting or worse vision. Prior to trabeculectomy 26 eyes
receiveda subconjunctival injection of 80 mg BCECF-AM followed by intraoperative
illumination with diffuse blue light (450-490 nm) for 8
minutes. The operation was used first in 10 patients and then extended to 16 more. In both groups, mean preoperative IOP in the
mid-30s was
reduced to the mid-teens postoperatively. Some eyes scarred and others required
medication to achieve IOP less than 21 mmHg. No serious
complications were encountered. The authors concluded that a prospective, randomized study is warranted.
Vitreous Amino Acid Levels in Patients with Glaucoma Undergoing
Vitrectomy RA Honkanen
University of Iowa.
Evidence for a role of excitatory amino acids in the progression of glaucomatous damage
has been a major underpinning of the rationale for
the investigation of a potential role of neuroprotective therapy in this disease. Recent events have case question on earlier
reports of
elevated glutamate levels in the vitreous of patients with glaucoma. Honkanen
measured amino acid levels in undiluted vitreous samples of 3
open-angle and 5 chronic angle closure glaucoma patients undergoing
vitrectomy. For controls, 17 specimens from eyes of non-diabetic patients without any glaucoma diagnosis were selected.
Concentrations of 16 amino acids were analyzed. P-values were adjusted by the number
of amino acids using Bonferroni's method; adjusted p-values << 0.05 were considered
significant. None of the 16 amino acids including
glutamate and glycine were significantly elevated in the vitreous of glaucoma eyes compared to controls. The alanine concentration
in
glaucoma eyes was higher than that of controls, and approached statistical significance.
One hypothesis presented as to why these
results might be different from the earlier results of Dreyer et al was that glutamate pyruvate transaminase, which converts glutamate to
alanine, might have played a role.
Studies on the role of endothelin-1 related vasospasm in
glaucoma M.T. Nicolela, Dalhousie
University, Halifax, Nova Scotia.
Vasospasm has been associated with glaucoma, although the mechanism and consequences of vasospasm in the development of glaucomatous damage
remains unknown. Nicolela investigated the possibility that abnormally high levels of thevasoconstrictor endothelin-1 (ET-1), which is
involved in Raynaud's phenomenon, cerebral vasospasm, diabetes, and ischemic heart disease, might be involved in glaucoma.
Twenty-five patients with glaucoma, 21 normal controls and 6 nonglaucomatous
patients with Raynaud's disease underwent total body surface cooling. Blood was collected before
and after the cooling test and plasma ET-1
was determined by immunoassay. Visual fields and retinal blood flow (Heidelberg Retina Flowmetry) were measured before and after
cooling.
Baseline ET-1 levels were not significantly different between glaucoma and
controls. Glaucoma patients, however, had a significant increase in
ET-1 after cooling, whereas controls did not. Glaucoma patients also had a significant reduction of retinal blood
flow in the temporal
region (mean decrease of 5.5%, p=0.05), not observed in normal controls. ET-1 levels in Raynaud's patients also tended to increase.
The author hypothesized that vascular endothelial dysfunction might to abnormal release of ET-1
under certain conditions, which could
adversely affect ocular blood flow.
Interleukin-1 alpha is produced by cultured trabecular meshwork cells after phacoemulsification ultrasound exposure N Wang, SK Chintala, MA Page, ME Fini, JS Schuman Tufts University School of Medicine, Boston, MA.
IOP often decreases after phacoemulsification. Wang et al tested the hypothesis that this
might be due to induction of stress cytokines such
as interleukin-1 alpha (IL-1 alpha). Normal and glaucomatous trabecular meshwork (TM) cells were isolated either from
cadaver or trabeculectomy
specimens. Confluent cultured TM cells were treated with an ultrasonic IA tip with or without phacoemulsification power for 60 seconds, or
left untreated. Cell conditioned medium was collected between 4 and 40 hours following treatment. IL-1
alpha levels were determined using an ELISA KIT. IL-1 alpha was not produced by normal
untreated TM cells, but was significantly increased in normal TM cells treated with phaco
ultrasound power. Treatment did not disrupt cells. Consistent with earlier findings,
glaucomatous TM cells produced IL-1 alpha constitutively and the level did not change
significantly with treatment (n=4). These results suggest that normal TM cells synthesize
IL-1 alpha in response to the stressful stimulation of phacoemulsification. Since IL-1 alpha
may increase outflow facility, it may play a role in the reduction of IOP after
phacoemulsification.
