MOTOR VEHICLE ACCIDENTS and GLAUCOMA

 

Glaucoma is a condition characterized by deterioration in the patient’s quality of life, relative to the progression of the disease. Some studies have reported that glaucoma patients are at increased risk of motor vehicle accidents (MVA).

A study has shown that drivers with severe binocular field loss, as determined by a screening test administered 40° nasally and 60° temporally at motor vehicle licensing offices, are approximately two times more likely to be involved in a crash than those with no field loss. [1]

There is a conventional notion in clinical practice that the eye with better function dictates visual performance. However, a study by McGwin et al. has shown that the worse eye’s visual field characteristics were significantly associated with crash involvement, whereas those of the better eye were not. [2]

The study evaluated the association between visual field defects in the central 24° field and the risk of MVAs among patients, 55 years or older, with glaucoma. The control set included glaucoma patients who were never involved in an MVA. For each patient, an Advanced Glaucoma Intervention Study (AGIS) score was calculated on automated visual fields collected with the 24-2 or 30-2 programs.

Each eye was studied separately. When compared with individuals with no VF defects, in the case of the better-seeing eye of the patient having severe VF defects (scores 12-20) there was an increased risk of an MVA (odds ratio [OR] 3.2, 95% CI 0.9–10.4), although the association was not statistically significant. Moderate (6–11) or minor field defects (1–5) in the better eye were not associated with the risk of involvement in a crash.

However, when studying the worse eye of the patient, patients with moderate or severe field defects were at significantly increased risk of an MVA (OR 3.6, 95% CI 1.4–9.4 and OR 4.4, 95% CI 1.6–12.4, respectively) compared with those with no defects. However, minor field defects in the worse eye did not increase the risk of an MVA (OR 1.3, 95% CI 0.5–3.4).

The study concluded that patients with glaucoma who have moderate or severe visual field impairment in the central 24° radius field in the worse-functioning eye are at increased risk of involvement in a vehicle crash.

REFERENCE:

[1] Johnson CA, Keltner JL. Incidence of visual field loss in 20,000 eyes and its relationship to driving performance. Arch Ophthalmol. 1983;101:371–375.

[2] McGwin G Jr, Xie A, Mays A, Joiner W, DeCarlo DK, Hall TA, Owsley C. Visual field defects and the risk of motor vehicle collisions among patients with glaucoma. Invest Ophthalmol Vis Sci. 2005 Dec;46(12):4437-41. doi: 10.1167/iovs.05-0750. PMID: 16303931.

IMMUNE MECHANISM MEDIATED GOA

 

Glaucoma is commonly associated with raised intraocular pressure (IOP). However, it is known that some patients develop/progress glaucomatous neurodegeneration in the absence of raised IOP. This has led to various non-pressure-mediated theories, such as vascular, biochemical, and inflammatory, responsible for glaucomatous optic atrophy (GOA).

Another possibility is that pathophysiological stress, such as that induced by elevated IOP, triggers secondary immune or autoimmune responses, leading to retinal ganglion cell (RGC) and axon damage even after the initial insult is gone.

The evidence for an autoimmune component in glaucomatous neurodegeneration includes the presence of a wide range of serum auto-antibodies particularly those against heat shock proteins (HSPs) and retinal deposits of immunoglobulins in glaucoma patients and animal models of glaucoma.

Experimental studies report inoculation of rats with human HSP27 and HSP60 induces an optic neuropathy that resembles glaucomatous neural damage, and elevated IOP has been reported to induce expression of HSPs in the retina, particularly RGCs.

 Therefore, there is a possibility of an association between IOP elevation, HSP upregulation, and induction of anti-HSP autoimmune responses in glaucoma.

It is also thought that the anti-HSP immune responses are induced originally by bacterial HSPs, and are reactivated by host HSPs during glaucoma. The facts that glaucoma patients exhibit increased titers of antibodies against Helicobacter pylori and that immunization with HSPs in rats induces glaucomatous neural damage are in line with this possibility.

In a study performed by Chen et al, microbeads (MB) were injected in the anterior chamber to increase IOP in one study population of mice. The control group was injected with saline.

The retina in the MB group showed infiltrating T-cells at 2 weeks after MB injection. The T-cells were scattered throughout the retina without apparent clustering or preference to any specific quadrant. The number of T cells then declined by 4 weeks.

During the infiltrative period, the glaucomatous retina also showed CD4+, but not CD8+, T cells in the ganglion cell layer (GCL), CD11b+ microglia, and macrophages.

The RGC and axon loss continued up to 8 weeks after MB injection, the longest time point that the mice were monitored. These results show that a transient elevation of IOP induces T cell infiltration into the retina and a prolonged period of retinal neurodegeneration, even after the IOP has returned to the normal level.

The study demonstrated that:

(1) a transient elevation of IOP is sufficient to induce CD4+ T-cell infiltration into the retina;

(2) T-cell responses are essential in the development of progressive GOA following IOP elevation;

(3) both bacterial and human HSPs are target antigens of these T cells; and 

(4) HSP-specific CD4+ T-cell responses and glaucomatous neurodegeneration are both abolished in mice raised in the absence of commensal microbial flora (germ-free (GF) mice), supporting a mechanism of bacteria-sensitized T-cell responses underlying the pathogenesis of glaucoma.

These observations identify a sequence of events that contribute to progressive GOA, implicating immune mechanisms, possibly in response to commensal flora.

REFERENCE:

Chen H, Cho KS, Vu THK, Shen CH, Kaur M, Chen G, Mathew R, McHam ML, Fazelat A, Lashkari K, Au NPB, Tse JKY, Li Y, Yu H, Yang L, Stein-Streilein J, Ma CHE, Woolf CJ, Whary MT, Jager MJ, Fox JG, Chen J, Chen DF. Commensal microflora-induced T cell responses mediate progressive neurodegeneration in glaucoma. Nat Commun. 2018 Aug 10;9(1):3209. doi: 10.1038/s41467-018-05681-9. 

ELEVATED GD15 IN GLAUCOMA

 

Dysregulated levels of growth/differentiation factor-15 (GDF15), a divergent member of the transforming growth factor-beta (TGF-β) superfamily, are associated with the pathology of various diseases. GDF15 is often induced under stress and with aging. The human trabecular meshwork cells express and secrete GDF15, suggesting its plausible role in regulating IOP.

In a study performed by Maddala and colleagues at Duke University, USA, the serum and aqueous humor (AH) levels of GD15 were compared between glaucoma and non-glaucomatous, cataract populations.

The GDF15 levels in AH and serum samples from primary open-angle glaucoma (POAG) patients were significantly elevated (p < 0.001 and p < 0.011, respectively) by > 9-fold and 1.5-fold, respectively, compared to the respective samples derived from non-glaucoma (cataract) patients. This held true for mild, moderate, and severe glaucoma patients.

AH GDF15 levels were significantly (p < 0.001) elevated in both male (by 11.6-fold) and female (by 5.4-fold) POAG patients compared to cataract patients.

For the serum GD15 levels, although there was an increase (median values: 2228.0 pg/mL, n = 19) in male POAG patients compared to male cataract patients (1850.0 pg/mL, n = 19), the difference did not achieve statistical significance (p < 0.148). Serum GDF15 levels in female POAG patients (n = 22), however, were significantly (p < 0.015) elevated (by 64%) compared to female cataract patients (n = 13).

This study reveals a significant and marked elevation of GDF15 levels in the AH of POAG patients compared to non-glaucoma cataract control patients. This may suggest a role of inflammation in the causation of glaucoma.

REFERENCE:

Maddala, R.; Ho, L.T.Y.; Karnam, S.; Navarro, I.; Osterwald, A.; Stinnett, S.S.; Ullmer, C.; Vann, R.R.; Challa, P.; Rao, P.V. Elevated Levels of Growth/Differentiation Factor-15 in the Aqueous Humor and Serum of Glaucoma Patients. J. Clin. Med. 2022, 11, 744. https://doi.org/ 10.3390/jcm11030744