Reducing intraocular pressure (IOP) is the only evidence-based intervention that can delay the onset and progression of glaucoma, which is sight threatening progressive optic neuropathy [1–2]. A major risk factor for glaucoma is an elevated IOP which is specified as values measured above 21 mmHg. Nevertheless, we know that rather than having an absolute high IOP above 21 mmHg, many patients suffer from an individual high IOP presenting with normal IOP ranges accompanied by glaucomatous damage and disease progression. Especially IOP-fluctuations, defined as the difference between maximal and minimal IOP values measured during a day, are relevant for progression in glaucoma damage [3–6]. Daily IOP-fluctuations ranging from 3.17 to 5 mmHg are considered to be physiological [7]. In contrast, glaucoma patients can show larger IOP variations ranging from 4.8 to 11 mmHg. According to other studies, IOP-fluctuation was not an independent risk factor of glaucoma or glaucoma progression [8–10]. Evaluation of IOP-values and their diurnal and nocturnal fluctuations can be performed in form of diurnal-nocturnal–IOP-profiles (DNP) [11]. Especially nocturnal IOP-measurements, which cannot be provided in an outpatient setting but often show nocturnal IOP-peaks, are of special relevance for the therapy of glaucoma patients [12–13].

Trabeculectomy (TE) augmented with mitomycin C (MMC) remains one of the most popular and effective IOP-lowering surgical techniques for open-angle glaucoma [14]. However, only few studies have examined the effect of TE with MMC on IOP-fluctuations in the course of diurnal-nocturnal-IOP-profiles [15–16]. Therefore, the aim of our study was to analyse the influence of TE with MMC on IOP values and IOP-fluctuation measured during a preoperative and postoperative 48-hour-DNP-IOP-profile. Additionally, the relationship between IOP parameters and other ophthalmological relevant factors, such as lens status, was evaluated.

This retrospective study was carried out in accordance with the Declaration of Helsinki. Ethics approval was obtained from the Ethics committee of Rhineland-Palatinate, Germany, which waived the requirement for informed consent of the included subjects. All patients had been treated and evaluated at the Department of Ophthalmology of the University Medical Center of the Johannes Gutenberg University Mainz. We performe about 1500 diurnal-nocturnal IOP profiles per year.

92 eyes of 92 patients were enrolled in this study. 62 (67.4%) of patients were female. The mean age at the time of TE with MMC was 64.71 ± 10.5 (range 35–82) years. 50 (54.3%) right eyes and 42 (45.7%) left eyes were included. 63 (68.5%) study eyes had POAG, 19 (20.7%) PEXG, 6 (6.5%) PG, 2 (2.2%) NTG and 2 (2.2%) eyes were suffering from juvenile glaucoma.

Table giving a summary of raw data can be found in the supplementary material (S1 Table).

The mean CCT of all study eyes was 523.6 ± 36 μm (range 444 to 625 μm).

At the time of the “preoperative” DNP 67 (72.8%) study eyes were phakic and 25 (27.2%) pseudophakic. At follow-up 57 (62%) study eyes were phakic. Ten patients had a cataract surgery on the study eye during the time between the first and the second DNP, so that 35 (38.0%) eyes were pseudophakic during the “postoperative” DNP.

“Preoperative” DNP trabeculectomy was performed in 12 (13%) fellow eyes, while „postoperative” DNP trabeculectomy has been performed in 25 (27.2%) of fellow eyes.

The “preoperative” DNP was performed at least 4 weeks and maximally 8 weeks before TE (mean 5.9 ± 1.4 weeks, range: 4–8 weeks). The “postoperative” DNP was performed at least six months after TE (mean 12 ± 5.7 months, range: 6–24 months). During the “preoperative” DNP all study eyes were treated with topical antiglaucomatous agents. Five different groups of antiglaucomatosa (beta-blockers, alpha-agonists, carbonic anhydrase inhibitors, prostaglandins, parasympathomimetics) were used either in monotherapy or in combination. At the timepoint of the 1st DNP on average 3.22 ± 0.94 substances were applied to the study eye. 40 (43.5%) patients received 4.32 (34.8%) 3 and 12 patients (13.0%) received 2 IOP lowering topical substances. A monotherapy was used in 6 (6.5%) patients and 2 (2.2%) patients applied 5 substances. At the timepoint of the 2nd DNP the majority of the patients were not using antiglaucomatous medication on the study eye (75 patients// 81.5%). Only 17 (18.5%) patients required on average 0.41 ± 1.00 (from 0 to 4 substances) antiglaucomatous agents (Table 1).

On average 0.74 ± 0.88 SL (range 0–4) and 3.30 ± 2.61 5-FU injections (range 0–10) were performed during the immediate postoperative period. Eight (8.7%) study eyes were treated with a needling procedure in the period between TE and the 2nd DNP. None of the patients needed re-trabeculectomy in this period.

The aim of our study was to investigate the influence of TE with MMC on IOP and IOP fluctuations measured by diurnal-nocturnal IOP profiles. To the best of our knowledge this is the first study evaluating 48-hour DNPs in this context. We recorded a statistically significant reduction of both postoperative mean IOP values and postoperative mean IOP fluctuations. More than 70% of the included patients demonstrated a mean diurnal/nocturnal IOP below 15 mmHg without use of additional topical antiglaucomatous therapy during the second DNP. A postoperative decrease above 30% of preoperatively medicated mean IOP was achieved in almost half of the patients without applying additional antiglaucomatous agents. Moreover, the post-TE IOP-curves markedly flattened during day and also nighttime. The postoperative IOP fluctuations were significantly reduced in comparison to preoperative values. This effect was more pronounced at nighttime than at daytime.

Klink et al. [15] retrospectively analysed pre- and postoperative 24-hour DNPs of 35 patients after undergoing TE with or without antimetabolites. In comparison to our study showing an IOP-reduction of 31.8%, they were able to demonstrate a higher postoperative IOP reduction of 40.0% during daytime. This is probably due to the higher maximal preoperative IOP-values evaluated by Klink et al. (26.5 ± 5.9 mmHg at daytime and 23.4 ± 5.2 mmHg at nighttime under 2.0 ± 1.2 antiglaucomatous agents) in comparison to our study population. However, IOP-reduction of 32% at nighttime correlated in both studies. Most of our study patients had a mean preoperative medicated IOP of less than 21mmHg or even 18 mmHg, but less than a quarter had a medicated IOP of less than 15 mmHg. We defined our postoperative target IOP below 15 mmHg. This restrictive endpoint was achieved in over 80% of the patients.

Only few studies have analysed the influence of filtering surgery on IOP-fluctuations. Klink et al. found a postoperative bisection of IOP-fluctuations to the level of 6.1 ± 1.6 mmHg at daytime and 3.9 ± 4.1 mmHg at nighttime. Saiz et al. found that both the maximum IOP and the amplitude of the IOP oscillations were significantly reduced one and five years after TE [19]. Wilensky et al. included 9 patients performing home tonometry using a Zeimer self-tonometer for at least 3 days before and at least 3 months after filtering surgery [16]. He found a lowering of the mean diurnal IOP from 21.3 ± 1.3 preoperatively to 12.3 ± 1.1 mmHg postoperatively, as well as a reduction of the day-to-day variability from 5.0 ± 0.6 to 2.4 ± 0.5 mmHg after filtering surgery. Unfortunately, the filtering surgery technique was not described in this study. Additionally, there is no information on the amount of used topical antiglaucoma therapy or additional glaucoma surgery.

All patients included in our study underwent primary TE augmented with MMC performed in the same manner. No other glaucoma surgery or laser trabeculoplasy had been performed in the study eye previously. IOP measurements performed beyond the office hours allow a reliable assessment of therapy success or failure in glaucoma patients. Among other things, they allow the assessment of nocturnal IOP-values in supine position, which are known to be frequently higher than daytime IOP-values measured in a sitting position [20]. Whether repeated IOP measurements beyond 24 hours provide relevant additional information, is currently under discussion [21]. When evaluating the IOP measurements registered in non-operated eyes, statistically significant lower mean IOP-values could be found on the second day in comparison to the first day of the performed DNP. This may be due to both psychological and physiological factors. Therefore, we are convinced that 48-hour DNP are superior to 24-hour IOP profiles. About 1500 diurnal-nocturnal 48-hour IOP profiles are performed in the Department of Ophthalmology of the University Medical Center of the Johannes Gutenberg University Mainz per year. They allow us to prove the efficacy of the topical therapy, as well as to justify the necessity of glaucoma surgery.

In his recent review Konstas et al. supports the advantages of 24 hour IOP-profiles in glaucoma management [22]. They enhance our understanding of the role of elevated IOP in glaucoma initiation and progression. With regard to our results, IOP oscillations can be more easily recognized by measurements performed throughout a 48-hour period. In contrast to the “preoperative” DNP we could not detect any significant IOP-differences between day 1 and 2 of the DNP during the “postoperative” DNP. This effect confirms the stable long-term IOP-reduction achieved with TE with MMC.

Documentation of IOP_max—the highest documented IOP, which was measured with or without therapy during the whole patient´s glaucoma history—facilitates assessment of the individual target IOP. In the present study the mean IOP_max showed a slight positive correlation with the mean IOP_total and mean IOP fluctuation_total in the preoperative DNP. We can speculate that patients with higher IOP_max benefit from a continuous measurement to a higher degree due to the fact that irregularities of IOP parameters may be detected with a higher precision during DNP. IOP_max also showed a slight positive correlation with the IOP-lowering effect of TE with MMC (ΔIOP). Patients with higher IOP_max had a larger benefit from the filtrating surgery. The incidence of immediate postoperative SL showed a slightly negative correlation with the TE-associated long-term pressure reduction (ΔIOP). Therefore, frequent SL could indicate inadequate long term filtration. Interestingly, TE in pseudophakic eyes seems to be less successful in comparison to phakic eyes [23]. Pseudophakia was associated with higher IOP fluctuation_total after TE with MMC compared to phakic patients. The difference was statistically striking, but clinically small. Additionally, the effect of TE with MMC on Δfluctuation in preoperatively pseudophakic patients was lower than in phakic patients.

The limitation of our study is a lack of further nighttime IOP-measurements. To evaluate the nocturnal IOP fluctuations accurately, repeated IOP measurements at several times during the night would be desirable. Furthermore, a prospective trial with a longer follow-up and better defined time points of postoperative DNPs (e.g. 6, 12, 18, 24 months) and assessment of functional parameters, such as visual field, should be considered.

In conclusion, we showed high efficacy of TE with MMC to lower IOP values and IOP fluctuations at both day- and nighttime for at least six months postoperatively. The remarkable IOP differences between the first and the second day of the DNP in non-operated eyes imply the necessity of IOP profile that last longer than 24 hours.