Graefe's Archive for Clinical and Experimental Ophthalmology

https://doi.org/10.1007/s00417-020-04672-1

GLAUCOMA

Impact of laser iridotomy on headache symptoms in angle-closure

subjects
Filipa Jorge Teixeira 1,2 & Filipa Caiado Sousa 1,2 & Nuno Pinto Ferreira 1,2 & Raquel Esteves Marques 1,2 &
Rafael Correia Barão 1,2 & Luís Abegão Pinto 1,2,3

Received: 21 December 2019 / Revised: 26 March 2020 / Accepted: 30 March 2020

# Springer-Verlag GmbH Germany, part of Springer Nature 2020

Abstract
Background Migraine symptoms are frequently referred by glaucoma patients. Although most studies analyze headache in the
acute setting of angle closure, many patients with chronic occludable angles also complain of headaches. The aim of this study
was to determine the impact of laser peripheral iridotomy (LPI) on the magnitude and frequency of headache symptoms in
patients with occludable angles.
Methods Prospective cohort study. Patients with indication for prophylactic LPI due to occludable iridocorneal angle were
included. Headache symptoms were assessed before and at least 4 weeks after LPI using the Headache Impact Test-6 (HIT-6)
questionnaire. A HIT-6 score of ≥ 50 points was labeled as a clinically significant headache.
Results Thirty-one subjects were included. Prophylactic LPI was performed in 60 eyes, as 2 patients were pseudophakic in the
fellow eye. Baseline HIT-6 score was 59.9 ± 11.8, with over three quarters of these patients scoring higher than 50 points (n = 24).
A statistically significant reduction in HIT-6 score was found after LPI treatment (45.4 ± 7.7, p < 0.01). Sub-analysis within the
clinically symptomatic subjects disclosed a significant improvement after treatment in this group (baseline, 65.3 ± 6.2 vs post-LPI
46.2 ± 8.3, p < 0.01), with a high baseline HIT-6 score being predictive of a symptomatic improvement after LPI (χ2(8) = 15.3,
p = 0.001). This is mimicked from the patient’s perspective, as the two subjective questions after LPI, concerning pain intensity
and frequency, report that 79.2% had a statistically significant improvement of the headaches.
Conclusions Within our sample, the majority of patients with occludable angles had clinically relevant headaches. LPI provided
symptomatic relief in the majority of those patients with high HIT-6 scores. Further studies are needed to explore the relationships
between headache and angle anatomy.

Keywords Occludable anterior chamber angles . Headaches . Laser peripheral iridotomy . Gonioscopy

Introduction

Patients referred to Glaucoma Departments are frequently

Filipa Jorge Teixeira and Filipa Caiado Sousa contributed equally to this enquired about the existence of headaches, as it is known that
work. glaucoma patients present a higher frequency of migraine-like
Filipa Jorge Teixeira and Filipa Caiado Sousa should be considered joint complaints [1–5]. Migraine is a disorder of both neural and
first authors. vascular involvement as part of its pathophysiology [6], and
the pain is attributed to the activation and sensitization of the
* Luís Abegão Pinto trigeminovascular system [7]. Indeed, while no mechanism
abegaopinto@gmail.com
has been identified for the pathophysiologic link between
1
Ophthalmology Department, Hospital de Santa Maria, Avenida
glaucoma and migraine, a likely vascular-related association
Professor Egas Moniz, 1649-035 Lisbon, Portugal may exist. Several authors have suggested a common vaso-
2
Clínica Universitária de Oftalmologia, Faculdade de Medicina,
spastic mechanism between normal tension glaucoma and mi-
Universidade de Lisboa, Lisbon, Portugal graine [8–10]. In this subset of patients, a vascular dysregula-
3
Centro de Estudos das Ciências da Visão, Universidade de Lisboa,
tion is thought to elicit the migraine as occurs in patients with
Lisbon, Portugal vasospastic disorders such as Raynaud’s phenomenon and

angina [8, 11]. Moreover, patients with acute angle closure
also typically present with a headache involving the area of
the ipsilateral superior branch of the V cranial nerve relating to
a sudden elevation of intraocular pressure (IOP) caused by an
acute occlusion of the iridocorneal angle [12, 13]. Laser pe-
ripheral iridotomy (LPI) is part of the treatment algorithm for
this condition, with a significant chance of success in angle
opening [14]. However, the vast majority of patients with
occludable angles do not present with acute symptoms [15,
16]. As a result, most angle-closure management is done in the
consultation setting, where LPI is done prophylactically upon
diagnosis and risk assessment.
One difficulty in the analysis of the association of headache
with glaucoma maybe the fact that headaches are usually clin-
ically assessed by ophthalmologists as a binary topic (yes/no)
and thus usually undervalued. However, headaches present a
major public health problem with more than 50% of the
European population having active headaches and with an
estimated 16% reduction in school and work productivity
[17, 18]. There are a number of tools developed to assess the
impact of this cumbersome symptom on the patient’s quality
of life (QoL). The Headache Impact Test-6 (HIT-6) is a reli-
able and valid tool for measuring the impact of headache on
daily life in both episodic and chronic migraine sufferers and
can be readily integrated into clinical practice, or clinical stud-
ies of migraine patients [19, 20].
The primary outcome of this study was to determine the
impact of LPI on headache symptoms using the HIT-6, in
patients with occludable angles. Secondary outcomes includ-
ed the impact of LPI in the frequency and intensity of head-
aches perceived by the patient. Furthermore, exploratory anal-
ysis was undertaken to identify risk factors associated with
headache-related symptoms and identification of predictive
factors of symptomatic improvement after LPI.
Methods
A prospective, cohort study with patients with occludable
angles was conducted at a tertiary hospital. A consecu-
tive group of patients were recruited from the general
ophthalmology and the glaucoma clinic from January
2017 to June 2018. Inclusion criteria included patients
with an indication for LPI, encompassing primary
angle-closure suspects (PACS), primary angle closure
(PAC), and angle-closure glaucoma (ACG) patients, age
over 18 years and willingness to sign an informed con-
sent. Angle classification followed the criteria set by the
current European Glaucoma Society guidelines [21].
PACS was defined as ≥ 180° iridotrabecular contact
(ITC), normal IOP, and no optic nerve damage; PAC as
≥ 180° ITC with peripheral anterior synechiae (PAS) or
elevated IOP, but no optic neuropathy; and PACG as ≥
Graefes Arch Clin Exp Ophthalmol
180º ITC with/without PAS, with elevated IOP, and optic
neuropathy. The eyes were excluded if PAS were present,
history of prior ocular surgery (including
phacoemulsification), contraindication to LPI, high ame-
tropias (myopia > 6 diopters and hyperopia > 4 diopters),
as well as if patients presented any known neurological
condition (other than a possible migraine) or any disease
that could account for autonomic dysfunction (such as
diabetes mellitus). All procedures were followed in ac-
cordance with the ethical standards of the responsible
committee on human experimentation (institutional and
national) and with the Helsinki Declaration of 1975, as
revised in 2000. Informed consent was obtained from all
patients prior to inclusion in the study.
All patients underwent complete ophthalmological exami-
nation, including LogMAR visual acuity, Goldmann
applanation tonometry, biomicroscopy, and fundoscopy.
Gonioscopy was performed resorting to dynamic gonioscopy
with an indentation lens (G-4 Four-Mirror Gonio High Mag
Volk) [22], and angle grading was according to Shaffer’s clas-
sification [23]. All gonioscopies and the decision for the indi-
cation for LPI were performed by the same glaucoma special-
ist (LAP).
LPI was performed by a single physician (FCS) using a
standard procedure: with an Abraham lens in the superior re-
gion (from 11:00 to 01:00), using a neodymium-doped yttrium-
aluminum-garnet (Nd:YAG) Q-switched 1064-nm laser
(Laserex LQ 2106, Laserex Technologies Adelaide, SA,
Australia) [24]. One drop of pilocarpine 1% was instilled 20 mi-
nutes before treatment. The laser was set for a 0 off-set, energy
starting at settings of 2 mJ and then increased up to 4 mJ as
needed until the iris was fully perforated and a patent iridotomy
of approximately 200 μm was achieved. All patients were giv-
en topical dexamethasone q.d.s for 5 days [21]. The IOP was
checked 30 min after the procedure, and if needed, a topical
carbonic anhydrase inhibitor was prescribed.
Evaluation after the LPI was performed by the same glau-
coma specialist (LAP) after 1 week and at least after 1 month
post-laser, with biomicroscopy, IOP, and gonioscopy
assessment.
The HIT-6 questionnaire was applied by a masked observer
to each patient at two separate time points: (1) prior to LPI
treatment and (2) 4–12 weeks after laser procedure. The HIT-6
questionnaire is shown on Table 1. The score for each ques-
tion uses a Likert-scale for the frequency of symptoms
allowing a score range from 36 to 78 points. It is considered
clinically relevant for a score ≥ 50 points [17, 18]. In the post-
treatment questionnaire, a two-set binary question (yes/no)
was added, questioning whether the patient had felt any im-
provement on (1) the intensity of the symptoms or (2) the
frequency of the headache episodes.
Mean and standard deviations (SD) or median and inter-
quartile ranges (skewed distributions) were reported for
Graefes Arch Clin Exp Ophthalmol

Table 1 Headache impact test-6. This questionnaire was designed to score the impact of headaches on patient’s life. The score is obtained by the sum of
points of the answer for each of the 6 questions.

1. When you have headaches, how often is the pain severe?

2. How often do headaches limit your ability to do usual daily activities including household work, work, school, or social activities?
3. When you have a headache, how often do you wish you could lie down?
4. In the past 4 weeks, how often have you felt too tired to do work or daily activities because of your headaches?
5. In the past 4 weeks, how often have you felt fed up or irritated because of your headaches?
6. In the past 4 weeks, how often did headaches limit your ability to concentrate on work or daily activities?
Scoring
Never Rarely Sometimes Very Often Always
6 points 8 points 10 points 11 points 13 points

continuous variables. Univariate comparisons were performed
with paired sample Student’s t test for continuous normally
distributed variables and the chi-square test for categorical
variables. A binary logistic regression model was applied to
determine whether or not there were predisposing factors for
the HIT-6 headache scores. A p value ≤ 0.05 was considered
statistically significant. Statistical analysis was performed
with SPSS (version 25.0, SPSS, Chicago, IL, USA).
Results
Thirty-one patients were included in the study with a
mean age of 56.5 ± 15.0 years old (range, 33–87) and
74.2% were female. In two patients, the fellow eye was
pseudophakic; therefore, prophylactic LPI was performed
only in the phakic eye, and thus rendering a total number
of 60 treated eyes. The eyes that were pseudophakic had
open angle; therefore, in these particular patients, the
migraine symptoms were only attributed to the fellow
eye with angle closure. The majority of the eyes had a
diagnosis of PACS (56.7%) with the remaining patients
having either PAC or PACG. Eleven patients (18.3%)
had plateau iris. Demographic and clinical characteristics
of these patients are reported in Table 2. No patient re-
ported headache symptoms at the day of the
questionnaire.
Patent iridotomy was achieved in all eyes in a single ses-
sion. The most frequent complications of LPI were bleeding
from the iridotomy site (10 eyes, 16.7%) and mild increase in
IOP (≤ 30 mmHg), during the first hour post-laser (9 eyes,
15.0%). Neither post-iridotomy dysphotopsia, refractive
changes, cataract, iridotomy closure, nor aqueous misdirec-
tion syndrome were reported. Post-LPI indentation
gonioscopy disclosed effective iridocorneal angle opening in
81.7% of the eyes. All 11 eyes that remained with occludable
despite a patent iridotomy had plateau iris. Previously to the
LPI, mean IOP was 16.0 ± 4.0 mmHg with a mild non-
significant reduction to 15.3 ± 3.3 after LPI (p = 0.25).
HIT-6 headache impact test scores
According to established HIT-6 questionnaire thresholds (HIT-6
score ≥ 50), 77.4% of the patients had clinically significant head-
aches before LPI, and after the LPI only 16.1% (p = 0.09). There
was a significant decrease in the scores from baseline (59.9 ±
11.8) to after LPI (45.4 ± 7.7); t(30) = − 6.8, p < 0.01.
A sub-analysis for the comparison of symptomatic (HIT-6
score ≥ 50) and asymptomatic patients detected an even great-
er magnitude in score improvement after the intervention in
the symptomatic subgroup (65.3 ± 6.2 vs 46.2 ± 8.3; t(23) = −
10.3, p < 0.01), with a mean decrease of 19 points from base-
line HIT-6 score. On the other hand, treatment showed no
effect in scoring in the subset of patients who were asymp-
tomatic at enrollment (41.1 ± 4.7 vs 42.5 ± 4.4; t(6) = 1.4, p =
0.22). The comparison of the HIT-6 score results between
these groups of patients is reported in Table 3.
Individual response to LPI relating HIT-6 scores is graph-
ically illustrated in a treatment effect (Fig. 1), which shows the
majority of the patients reporting significant improvement in
their symptoms, with most patients outside the indifference
line (i.e., treatment with no effect). This is mimicked from
the patient’s perspective, as the two subjective questions after
at least 1 month after bilateral LPI, concerning pain intensity
and frequency, report that 79.2% of the patients had a signif-
icant improvement in their headache-related symptoms.
Exploratory analysis with binary logistic regression for
the identification of factors associated with a HIT ≥ 50
showed no significant associations including gender,
age, baseline diagnosis, angle status, or IOP (p > 0.05).
Binary logistic regression was conducted for the identifi-
cation of predictive factors of symptomatic improvement
after LPI. The only parameter was a high baseline HIT
score, (χ2 (8) = 15.3, p = 0.001) with no other predictive
variable of symptomatic improvement, including gender,
 Graefes Arch Clin Exp Ophthalmol

Table 2 Demographic data

Mean (± SD) Range

Age (years) 56.5 ± 15.1 (33; 87)
Gender, n (%) Female, 23 (74.2%) | male, 8 (25.8%)
SE (diopters) + 1.64 ± 1.32 (0.00 − + 4.50)
BCVA (LogMAR) 0.07 ± 0.14 0.50–0.00
IOP pre-LPI (mmHg) 15.96 ± 3.94 8.00–24.00
IOP post-LPI (mmHg) 15.31 ± 3.28 8.00–22.00
Diagnosis (N eyes, %) PACS 34 (56.7%)
PAC 12 (20.0%)
PACG 14 (23.3%)
Plateau iris 11 (18.3%)
Schaffer grade, pre-LPI (N eyes, %) 0 6 (10.0%)
I 40 (66.7%)
II 14 (23.3%)
Schaffer grade, post-LPI (N eyes, %) II 11 (18.3%)
III 9 (15.0%)
IV 40 (66.7%)
Iridocorneal angle opening post-LPI (N eyes, %) Open angle, 49 (81.7%)
Occludable angle, 11 (18.3%)

BCVA, best corrected visual acuity; IOP, intraocular pressure; LPI, laser peripheral iridotomy; PACS, primary angle-closure suspect; PAC, primary angle
closure; PACG, primary angle-closure glaucoma; SE, spherical equivalent

age, baseline diagnosis, angle status, IOP, or HIT-6 score Discussion

(p > 0.05). However, it was noted that in the symptomatic
group, there was a predominance of women compared
with the asymptomatic group (male to female ratio of
3:21 vs 5:2), and patients were younger (54 vs 65 years
old). More than 90% of women included in the study
were symptomatic and were younger than 75 years old.
The majority of the subjects with occludable iridocorneal an-
gles in our sample presented clinically relevant headaches
(77.4%); this percentage is higher than the prevalence reported
in the literature for the overall population (10–15%) [17, 18].
Although some studies find no significant difference in

Table 3 Comparison between symptomatic and asymptomatic patients using the HIT-6 scoring system

Symptomatic (HIT ≥ 50) Asymptomatic (HIT < 50) p value

Patients, n (%) 24 (77.4%) 7 (22.6%)
Male:female ratio 3:21 5:2 < 0.01
Age (years) 54.0 ± 15.2 64.7 ± 4.4 0.07
SE (diopters) + 1.6 ± 1.4 + 1.8 ± 0.3 0.50
Diagnosis
PACS 16 2
PAC 4 2 -
PACG 4 3
Pre-LPI Post-LPI p value Pre-LPI Post-LPI p value
HIT-6 score 65.3 ± 6.2 46.2 ± 8.3 < 0.01 41.1 ± 4.7 42.5 ± 4.4 0.22
HIT-6 score mean difference − 19.1 + 1.4
Subjective improvement: frequency 19 (79.2%) 0 (0%)
Subjective improvement: intensity 19 (79.2%) 0 (0%)

HIT, Headache Intensity Questionnaire; SE, spherical equivalent; LPI, laser peripheral iridotomy; PACS, primary closure suspect; PAC, primary angle
closure; PACG, primary angle-closure glaucoma; SD, standard deviation
Graefes Arch Clin Exp Ophthalmol

Fig. 1 Individual HIT-6 score response to LPI. a Global analysis. b In asymptomatic patients (HIT-6 score < 50). c In symptomatic patients (HIT-6 score
≥ 50). HIT, Headache Intensity Test questionnaire; LPI, laser peripheral iridotomy

migraine prevalence between glaucoma and non-glaucoma
control groups, other epidemiological reports find migraine
as more common (~ 30%) in patients with glaucoma relative
to the general population; the reasons however remain unclear
[3–5, 8, 25]. It is known that the pain of migraine is attributed
to the activation and sensitization of the trigeminovascular
system [7, 8, 10]. Acute corneoscleral stretching by experi-
mental IOP elevations discharges impulses in the iris, cornea,
sclera, and whole nerve V1 fibers probably due to the mechan-
ical distortion of the iris and chamber angle [26]. This can
explain headaches associated to acute episodes of angle
occlusion [27]. However, as headaches are a chronic condition
with multiple monthly episodes, as depicted from the elevated
HIT scores in our sample, it would be unusual that symptom-
atic patients would endure long hours of elevated IOP
throughout large segments of their lives and still not show
signs of clinical damage to the optic nerve. Furthermore, our
data suggests that angle status is not necessarily related to high
baseline HIT scores, as a significant number (22.6%) of pa-
tients with occludable angle did not report symptoms.
Moreover, there was a score improvement even in patients
where LPI was unable to significantly widen the angle (as in

iris plateau). Additionally, some patients still reported head-
ache improvement despite being aware that the primary goal
of the LPI treatment was not reached (opening of the angle—
as were the cases of the iris plateau syndrome). This suggests
that the positive outcomes would not solely be related to in-
herent psychological factors associated with questionnaire
studies. Put together, our study suggests that there may be
individual factors that could either make subjects more aware
of any minor angle occlusions or, alternatively that any iris-
related spasms could act as a trigger for an underlying tenden-
cy to have a migraine. Indeed, the subjects within our sample
that more actively reported higher baseline HIT scores have a
significant demographic overlapping with the subjects more
prone to have migraines (e.g., young female individuals).
Interestingly, there was a significant improvement in pa-
tient complaints associated with LPI treatment, thus suggest-
ing that a mechanical mechanism may exist. In fact, it has
been demonstrated that removing a pupillary block is associ-
ated with a change in iris morphology, with a decreased con-
vexity and a straightening of the iris plane [28, 29]. One pos-
sibility could be that post-LPI, iris morphology becomes less
prone muscle spasms, possibly resetting any prior threshold
for migraine to a higher level. This would provide a rationale
as to why we detected a significant decrease in the HIT score
test in the symptomatic group of patients (from 65.3 ± 6.2 to
46.2 ± 8.3, p < 0.01), and in 79.2%, there was a decrease in the
number and frequency of migraines in these susceptible indi-
viduals. Indeed, there have been increasing data suggesting
mild inflammation of orbital and periocular muscles triggering
chronic migraine such as trochleitis or frontal muscle disor-
ders [30]. Furthermore, muscle-oriented therapies such as bot-
ulinum or myotomies of the frontal muscle are reported to be
effective in improving headaches [31, 32]. Regardless of the
mechanism, it would seem that in a patient-oriented setting,
actively questioning about migraine is of relevance in patients
with glaucoma, particularly the ones with an angle-closure
mechanism. Not only because it has been associated with
the disease, but also apparently because part of the treatment
strategy for angle-closure glaucoma can improve symptom-
atology for the QoL impacting headache [13, 33].
This study was designed as a proof of concept that patients
with chronic angle closure with headaches respond symptom-
atically well to treatment with LPI. However, there were cer-
tain limitations to the study. Quantitative data of the anterior
segment was not obtained which would be of the outmost
importance to understand the underlying mechanisms of this
intriguing relationship between angle closure and headache,
and hopefully help determine which subset of patients is more
likely to benefit from the procedure. Therefore, future pro-
spective studies should be conducted with the use of anterior
segment imaging (ultrasound biomicroscopy, anterior seg-
ment OCT, and pupillometry) so to properly quantify morpho-
logical parameters such as anterior chamber depth, iris
Graefes Arch Clin Exp Ophthalmol
curvature, lens thickness, and pupil size, and to analyze the
change of such parameters after performing iridotomy.
Moreover, further studies should be conducted to study as
well the impact of iridotomy in the QoL of these patients.
Additionally, in this study, migraine was a term used in a
self-reported basis as part of the questionnaire, which might
lead to some extent to a misdiagnosis of different types of
headaches as migraine. However, it is a term that has been
extensively used in several glaucoma epidemiologic studies
[34–36]; therefore, it was used in this study as well.
In conclusion, within our sample, the majority of patients
with occludable angles had clinically relevant headaches. LPI
appears to have provided symptomatic relief in a significant
proportion of patients. Further studies are needed to explore
the relationships between headache triggers and angle
anatomy.
Compliance with Ethical Standards
Conflicts of interest The authors declare that they have no conflict of
interest.
Ethics approval All procedures performed in studies involving human
participants were in accordance with the ethical standards of the institu-
tional and national research committee and with the 1964 Helsinki dec-
laration and its later amendments or comparable ethical standards.
Consent to participate Informed consent was obtained from all individ-
ual participants included in the study.
Consent for publication Patients signed informed consent regarding
publishing their data and photographs.
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