Beyond Pressure: Why Some Glaucoma Patients Keep Losing Vision at Target IOP

“The pressure is well controlled. We’ll keep monitoring.”

Every eye-care clinician has said it. And all too often, the fields keep narrowing anyway.

That is not a rare exception. Neeru Gupta and Yeni Yücel, at St Michael’s Hospital and the University of Toronto, wrote in 2007 that progressive vision loss among glaucoma patients is common despite effective pressure reduction. They concluded that mechanisms independent of IOP are also involved. A year earlier, their group examined, post-mortem, a man whose glaucoma had been recorded as stable at 8 mmHg on treatment. They found axon loss in both intracranial optic nerves, atrophy of the lateral geniculate nucleus, and thinning of the visual cortex in the region matching his field loss.

While pressure acts on the optic nerve, it is not the whole story.

Two sides of a damaged optic nerve

One side is the damaging factor. Often that is pressure. It can also be poor perfusion, oxidative stress, other factors and or a combination thereof. Drops, laser and surgery are intended to remove the damaging factor resulting from high IOP, and that is what they are for.

The other side is the nerve’s own capacity to repair. Retinal ganglion cells (RGCs) that are still alive are working continuously to maintain themselves. How well they manage depends on the conditions they work in, for instance: blood supply, cellular energy, neurotrophic support, and the inflammation around them. Where those conditions have deteriorated, removing the damaging factor may not be enough.

Standard care addresses the first side and then monitors. The second side is left to the body to manage on its own.

This article looks at some published clinical work on supporting that second side, alongside standard care. It also introduces coMra biosupport, a non-invasive way to bring that approach into practice.

What the nerve runs short of

RGCs don’t make their own brain-derived neurotrophic factor (BDNF), a protein that supports neuronal survival. It is carried back from the brain along the axon, and released locally around the vessels behind the eye. In 2000, Harry Quigley’s group at Johns Hopkins raised IOP in rats and found BDNF delivery cut by 74%, and by 83% at higher pressure.

Energy is another vulnerability. RGCs are among the most energy-demanding cells in the body. Rojas and colleagues (University of Texas, 2008) blocked mitochondrial energy production in rats’ eyes with rotenone, a complex I inhibitor. Visual function fell, the nerve fibre layer thinned and RGCs were lost. Near-infrared light prevented all three, and higher doses protected more.

Cells under this kind of stress are alive but struggling. A struggling nerve is not a lost one.

The evidence: same pressure, different outcomes

Egorov and colleagues (Moscow and Saratov, 2016) followed 217 patients with primary open-angle glaucoma for a year. Everyone’s IOP was at target throughout. One group stayed on drops alone. The other also received a magnetic field with infrared laser, applied transcranially from the temples back, in four courses across the year.

• Drops alone: part of the retinal electrophysiological signal weakened at every stage of disease. BDNF fell at the early and advanced stages.
• Drops plus treatment: the retinal signal and the visual field improved at all three stages, and BDNF rose at every stage. The neuroretinal rim held at the earliest stage and thinned slightly at later stages, significantly less than on drops alone.

Visual field mean deviation tells the same story. At the advanced stage it improved from 13.7 to 11.1 dB with treatment, and worsened to 15.7 dB on drops alone.

Full results table: Egorov 2016, all measures after one year

217 patients with primary open-angle glaucoma, stages I–III, followed for one year with pressure at target in both groups. Treated: drops plus dynamic transcranial magnetotherapy and laser stimulation, four courses over the year. Drops alone: hypotensive drops only. Each stage has one baseline value (“Before”), shared by both groups, then each group’s value after one year.

Stage I (early)

Measure	Before	Treated 1 year	Drops alone 1 year
PERG P50 latency (ms)	52.01± 1.94	52.43± 2.08	54.21± 4.15
PERG N95 latency (ms)	95.91± 9.7	96.11± 10.3	98.34**± 5.2
PERG P50 amplitude (µV)	4.23± 0.8	5.02*± 0.7	3.5**± 0.8
PERG N95 amplitude (µV)	7.12± 1.2	8.96*± 1.03	7.14**± 2.15
PhNR latency (ms)	82.26± 5.7	77.81*± 6.3	80.81**± 3.6
PhNR amplitude (µV)	92.03± 5.1	95.19*± 7.1	86.22**± 9.1
BDNF (serum)	65.7± 5.3	89.9*± 9.7	44.9**± 11.5
CNTF (serum)	9.4± 1.3	17.5*± 7.2	11.7**± 5.2
Neuroretinal rim volume, RV (mm³)	0.341± 0.12	0.342± 0.24	0.328**± 0.36
Visual field mean deviation, MD (dB)	3.4± 1.75	2.4*± 1.25	3.9**± 1.67

Stage II (moderate)

Measure	Before	Treated 1 year	Drops alone 1 year
PERG P50 latency (ms)	57.9± 6.2	54.8*± 6.7	58.6**± 4.2
PERG N95 latency (ms)	111.98± 7.8	99.98*± 7.3	108.66**± 9.9
PERG P50 amplitude (µV)	2.62± 1.2	3.71*± 1.1	2.01**± 6.3
PERG N95 amplitude (µV)	3.8± 1.3	4.91*± 1.1	3.67**± 1.5
PhNR latency (ms)	84.56± 7.4	82.96*± 6.8	93.5**± 6.9
PhNR amplitude (µV)	84.6± 8.9	89.1*± 6.2	80.1**± 3.2
BDNF (serum)	73.4± 6.9	97.6*± 8.9	75.12**± 7.4
CNTF (serum)	9.7± 4.4	13.2*± 9.9	10.2**± 8.6
Neuroretinal rim volume, RV (mm³)	0.288± 0.23	0.282± 0.23	0.270**± 0.75
Visual field mean deviation, MD (dB)	8.1± 3.2	6.8*± 2.2	9.1**± 1.8

Stage III (advanced)

Measure	Before	Treated 1 year	Drops alone 1 year
PERG P50 latency (ms)	59.8± 5.7	55.3*± 3.9	58.3**± 4.1
PERG N95 latency (ms)	113.9± 6.1	112.1± 4.6	118.1**± 8.6
PERG P50 amplitude (µV)	1.1± 0.1	1.9*± 0.1	0.7**± 0.8
PERG N95 amplitude (µV)	2.4± 0.4	3.13**± 0.2	2.7**± 0.4
PhNR latency (ms)	90.7± 3.2	86.23*± 3.9	94.23**± 5.1
PhNR amplitude (µV)	81.92± 4.7	83.12*± 5.7	71.54**± 6.9
BDNF (serum)	53± 8.3	58*± 4.9	36**± 5.6
CNTF (serum)	7.6± 2.8	7.9*± 4.5	6.1**± 9.0
Neuroretinal rim volume, RV (mm³)	0.164± 0.15	0.160*± 0.19	0.139**± 0.88
Visual field mean deviation, MD (dB)	13.7± 4.6	11.1*± 3.2	15.7**± 4.7

^* p < 0.05: the change from baseline is significant. ^** p < 0.05: the difference in change between the treated and drops-alone groups is significant.

Reading the table

• Latency (ms): shorter is better. Amplitude (µV): higher is better.
• PERG (pattern electroretinogram): N95 reflects retinal ganglion cell function most directly. PhNR (photopic negative response) is the ganglion cell component of the flash ERG.
• RV: neuroretinal rim volume on HRT tomography; higher is better.
• MD: visual field mean deviation as printed in the paper (positive values = loss); lower is better. Humphrey printouts show the same loss as a negative number.
• BDNF, CNTF: neurotrophic (nerve-survival) factors measured in blood serum. Units are not given in the printed table.

Source: Egorov EA, Kamenskikh ID, Kamenskikh TG, et al. RMJ Clinical Ophthalmology 2016;1:19–24, Table 2. In Russian; translated from the printed table.

Declining, holding and improving: all three appeared in one study, at the same pressure.

Both groups had their pressure controlled. What separated them was what happened at the cellular level, in the factors that determine whether neurons survive.

Sidelnikova and Kamenskikh (Saratov, 2014) treated 126 patients with a magnetic field and infrared laser over the drainage area, added to drops. Pressure came down and drainage improved in 73%. At the early and middle stages, scotomas shrank in 52% of treated patients. On drops alone, that change was seen only at the early stage, in 20%. In a quarter of treated patients, absolute defects became relative. Retrobulbar blood flow improved in 63%.

This is not fringe work. In Russia, these methods are part of comprehensive glaucoma care. The national guideline (Russian Glaucoma Society, 2013) devotes a full chapter to electrotherapy, magnetotherapy, phototherapy (including laser stimulation) and ultrasound, recommends them for glaucoma, and places them alongside drops or surgery, once pressure is controlled.

coMra biosupport

coMra combines low-level infrared laser, magnetic field, sequenced coloured LED light and, in some models, low-power ultrasound, applied together to the same volume of tissue at the same time. It follows on from magneto-infrared-laser (MIL) therapy, the infrared laser and magnetic field combination used in the studies above, and has seventeen years of use in practice and at home behind it, eyes among them.

coMra isn’t aimed at a specific pathology, and it doesn’t remove a damaging factor the way drops or surgery do. Instead it increases the efficiency of the body’s own self-repair, wherever that repair is falling behind, by improving the conditions that repair depends on. Red and near-infrared light, for example, is absorbed by cytochrome c oxidase, a key mitochondrial enzyme in retinal nerve cells, and increases the efficiency of their energy (ATP) production (Rojas and Gonzalez-Lima, 2011). That is the mechanism behind the protection seen in their 2008 study.

The body then does the rest. In the Sidelnikova study, the treated eyes functioned better: outflow increased and pressure came down in 73% of patients, alongside the gains in the nerve itself. The authors traced this to better microcirculation: blood flow behind the eye increased, and the ciliary body and choroid became more permeable, activating the eye’s second drainage route, the uveoscleral outflow. They link the infrared laser’s role to correcting local energy imbalance in the tissue. The approach supported the eye’s own repair, and the eye took care of more of the problem.

coMra is not intended to replace standard care. Standard care removes what is doing harm. coMra expands what care can do, by supporting the repair.

What to expect

• Earlier is better, but advanced isn’t lost. Treated over the drainage area, advanced eyes changed little. Treated transcranially, they improved, and in Egorov 2013 the advanced stage showed the largest visual field gain (74.4%). What remains of the nerve can work better. Tissue already lost does not come back.
• It is ongoing. Gains faded over months, so courses were repeated, mostly every three to six months.
• Responses vary. Some patients improved, some held, some did not change. In progressive disease, holding counts.
• The literature has limits. None of these studies used a sham control, and most come from one country.

Learn more

The coMra Eye Hub sets out the studies, the mechanisms, and how coMra fits alongside standard care: eye-hub.comra-therapy.com

Written by Garrett Murrin of Radiant Life Technologies, the company behind coMra. Every source is named for that reason.

References

• Gupta N, Yücel YH. Glaucoma as a neurodegenerative disease. Curr Opin Ophthalmol 2007;18(2):110–114. PMID 17301611
• Gupta N, Ang L-C, Noël de Tilly L, Bidaisee L, Yücel YH. Human glaucoma and neural degeneration in intracranial optic nerve, lateral geniculate nucleus, and visual cortex. Br J Ophthalmol 2006;90(6):674–678. PMID 16464969
• Quigley HA, McKinnon SJ, Zack DJ, et al. Retrograde axonal transport of BDNF in retinal ganglion cells is blocked by acute IOP elevation in rats. Invest Ophthalmol Vis Sci 2000;41(11):3460–3466. PMID 11006239
• Egorov EA, Kamenskikh ID, Kamenskikh TG, et al. Influence of dynamic transcranial magnetotherapy and laser stimulation on the activity of retinal ganglion cells and the level of neurotrophic factors. RMJ Clinical Ophthalmology 2016;1:19–24. In Russian.
• Egorov EA, Kamenskikh TG, Raigorodsky YuM, Kolbenev IO, Kamenskikh ID. The results of trans-cranial application of the low-intensity magneto-laser treatment in the patients presenting with primary open-angle glaucoma. Physiotherapy, Balneology and Rehabilitation 2013;12(5):15–18. In Russian. Journal page
• Sidelnikova VS, Kamenskikh TG. Evaluation of efficiency of dynamic laser magnetic stimulation of eye drainage system of patients with open angle glaucomatosis. Saratov J Med Sci Res 2014;10(2):336–340. In Russian, English abstract. Journal page
• Filatova VS, Kamenskikh TG, Zakharova NB. Efficiency analysis of laser magnetic stimulation of an eye drainage system in the treatment of patients with different stages of primary open angle glaucoma based on developments of functional indicators and biochemistry factors. Saratov J Med Sci Res 2017;13(2):406–411. In Russian, English abstract. Journal page
• Glaucoma: National Guidelines. Ed. Egorov EA. Russian Glaucoma Society. Moscow: GEOTAR-Media, 2013. Ch. 20, pp. 521–563. In Russian.
• Rojas JC, Lee J, John JM, Gonzalez-Lima F. Neuroprotective effects of near-infrared light in an in vivo model of mitochondrial optic neuropathy. J Neurosci 2008;28(50):13511–13521. PMID 19074024 · Free full text
• Rojas JC, Gonzalez-Lima F. Low-level light therapy of the eye and brain. Eye and Brain 2011;3:49–67. doi:10.2147/EB.S21391