(Investigative Ophthalmology and Visual Science. 2002;43:87-91.)
© 2002
by The Association for Research in Vision and Ophthalmology, Inc.
Reflex and Steady State Tears in Patients with Latent Stromal Herpetic Keratitis
Sander Keijser1,
Jaap A. van Best2,
Allegonda Van der Lelij1 and
Martine J. Jager1
1 From the Leiden University Medical Center, Department of Ophthalmology, Leiden, The Netherlands; and the
2 Department of Ophthalmology and Visual Sciences, Coimbra University, Coimbra, Portugal.
 |
Abstract
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PURPOSE. To compare tear production in patients with stromal herpetic keratitis
with that in healthy control subjects.
METHODS. After instillation of 2 µL fluorescein into both eyes, the
tear-fluorescein concentration was measured by fluorophotometry. During
the first 10 minutes, steady state tear turnover (TTO-1) was
determined. After a nasal alcohol stimulus to induce reflex tears, a
second steady state tear turnover (TTO-2) was obtained during 15
minutes. The index of reflex lacrimation (IRL) was calculated as the
percentage decrease in tear fluorescein concentration directly after
the stimulus. TTO-1, TTO-2, and IRL were determined in the patients’
affected eyes (n = 12), in the patients’ healthy
contralateral eyes, if possible (n = 9), and in one eye
of healthy control subjects (n = 24).
RESULTS. The TTO-1 in the affected and healthy eyes of patients was
approximately two times lower than the TTO-1 in eyes of healthy control
subjects (P = 0.012 and P =
0.024, respectively) and almost equal to the TTO-2 in eyes of healthy
control subjects (P = 0.32 and
P = 0.40). There were no significant differences in
the values of TTO-1, IRL, and TTO-2 between affected and healthy eyes
of patients (P > 0.5). IRL and TTO-2 did not
differ significantly among the three groups (P >
0.5).
CONCLUSIONS. Both eyes of the patients were dry. The dryness could be due to a
defective reflex lacrimation under physiological conditions that can
still be induced by nonphysiological nasal excitation. The cause of
this may be demyelination of both trigeminal root entry zones as a
result of a unilateral eye infection by the herpes virus. Another
possibility is that dryness predisposes to herpetic infection or
recurrent inflammation.
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Introduction
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Herpes simplex virus (HSV)-1 is the main infectious cause
of blindness in developed countries.1
2
In Europe, almost
80% of the adult population has antibodies against
HSV-1.3
4
Only a minority of the infected population has
active infections, such as herpes labialis or ocular herpes. In the
cornea, there are two main types of herpetic infection: epithelial
herpes and herpetic stromal inflammation. Patients with active
epithelial herpes or active stromal inflammation often report
hypersecretion of tears,5
6
whereas in our clinical
experience those with latent stromal inflammation report dryness. This
dryness may be caused by a failure in the production of tears by the
lacrimal glands, either by the main lacrimal gland, which is situated
in the superior lateral corner of the orbit, and/or by the accessory
lacrimal glands, which are situated in the upper fornix and in the
conjunctiva of the upper eyelid. Reflex tears are defined as the tears
resulting from external stimuli, such as cold wind or irritation by a
foreign body or irritating gas, or from internal stimuli, such as
stress and emotion. Basal tears are assumed to be the tears that are
produced at the lowest possible stimulation level of the tear glands.
Steady state tears are defined as tears under normal physiological
conditions7
and are supposed to be produced by main as
well as accessory lacrimal glands.8
9
10
In the clinic, steady state tears are usually evaluated using the
Schirmer I test and reflex tears with the Schirmer II test after nasal
stimulation. Although the Schirmer test is easy to perform, it is
inaccurate and not suitable for research
purposes.9
11
12
13
14
A standardized protocol to
accurately evaluate steady state tear production by using a scanning
fluorophotometer was described in 1994.15
A new method to
evaluate steady state and reflex tear production simultaneously was
developed recently.7
This method consists of (1)
measurement of the decay of fluorescein in tears during the first 10
minutes after instillation of 2 µL 2% fluorescein, (2) induction of
reflex lacrimation by delivering a standard amount of alcohol vapor to
both nostrils for 5 seconds, and (3) measurement of tear-fluorescein
decay for another 15 minutes. The relative decay of fluorescein in
tears (tear turnover; TTO) is expressed as the percentage decrease per
minute during steady state lacrimation. Reflex lacrimation is expressed
as the percentage decrease in tear fluorescein induced by the stimulus
(index of reflex lacrimation; IRL). TTO before stimulus, TTO after
stimulus, and IRL can be quantified by scanning
fluorophotometry7
(Fig. 1)
. Because in healthy individuals the secondary TTO is approximately
half the value of the primary TTO, the secondary TTO is thought to
consist mainly of basal tears.7
After the outpouring of
reflex tears after alcohol exposure, the main tear gland is considered
to have emptied.
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Figure 1. Relative concentration of tear fluorescein in an eye of a 21-year-old healthy volunteer versus time after instillation.
Dashed vertical lines at the left:
limits for determination of TTO-1; at right: limits
for determination of TTO-2; middle solid line: time of
alcohol stimulus; thick arrow: IRL at the time of the
stimulus, expressed as a percentage and obtained by forward and
backward extrapolation of first and second fluorescein concentration
decay.
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In our study, fluorophotometry was applied in patients with
latent stromal herpetic keratitis. Patients with active herpetic
epithelial infection were excluded, because affected epithelium could
stimulate reflex tears and mask a possible decrease in tear flow caused
by the infection. Although only one eye is usually affected in patients
with herpetic keratitis, both eyes were measured to be able to compare
the affected eye with the healthy eye.
Main and accessory glands can both be affected by the herpes simplex
virus (HSV), because HSV is capable of transporting itself along nerve
fibers,16
17
18
and both glands are
innervated.19
20
When both main and accessory glands are
affected, both basal tearing (indicated by the second steady state TTO)
and reflex tearing (indicated by the IRL) are decreased. The purpose of
this study was to determine both reflex and basal tears in patients
with stromal herpetic keratitis and to compare the data with those of
healthy volunteers to obtain information on the relationship between
stromal herpetic keratitis and tear secretion.
|
Methods
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Patients and Control Subjects
Twelve patients with latent stromal herpetic keratitis were
acquired from the outpatient clinic of the Leiden University Medical
Center. A group of 16 healthy volunteers from a recent reflex tear
study from the same clinic were recruited for comparison (one eye
per individual).7
Furthermore, eight healthy
volunteers from acquaintances, relatives, and members of the Department
of Ophthalmology staff of the hospital were added to the study
(both eyes were measured) to check the similarity of the
measurements. The mean age of the patients was 56.7 ±
13.9 years (SD), and the group consisted of seven men and five women.
The control group consisted of 13 men and 11 women, and the
average age was 47.6 ± 16.2 years. All participants had to
have a clear cornea on slitlamp examination and could not wear
contact lenses or have any systemic disease. Fluorescein should not
have been administered during the 76 hours before the test. Patients
were included in the study when latent stromal herpetic keratitis had
been clinically diagnosed. Ten of the 12 patients used topical
corticosteroids and oral valacyclovir. Three patients had previously
undergone corneal transplantation and two cataract extraction.
The study was conducted according to the principles of the Declaration
of Helsinki and was approved by the Medical Ethics Committee of the
Leiden University Medical Center. Informed consent was obtained from
all participants after explanation of the nature and possible
consequences of the study.
Instrumentation
Measurements were made with a scanning fluorophotometer
(Fluorotron Master; Ocumetrics, Mountain View, CA) equipped with a
special lens (Anterior Segment Adaptor) for detailed scanning of
corneal and tear fluorescence. A calibrated capillary tube (5 µL with
a 1-µL scale) was used to instill 2 µL fluorescein 2%. A
fluorescein standard (F-53; Zeiss, Oberkochen, Germany) was used to
check the fluorophotometer. The data were processed by software
developed at the Leiden University Medical Center (Reflex software
program).
Measurement Procedure and Calculations
Before measurements, an ophthalmologist examined the
surface of the cornea with a slitlamp without using fluorescein. The
fluorophotometer was turned on 20 minutes before measurements, and the
scanning time was adjusted to 6 seconds to enable measurements in both
eyes. First, four fluorophotometric prescans were made of both eyes to
determine the autofluorescence of the corneas. Then, 2 µL 2%
fluorescein was instilled in the cul-de-sac of both eyes, in the
temporal side of the lower fornix. During instillation, the eyes and
eyelids were not touched, to avoid reflex tearing as much as possible.
Time of instillation was noted. The subjects were asked to blink
without squeezing and to roll their eyes to distribute the fluorescein
homogeneously. Five minutes were awaited to minimize a possible effect
of reflex lacrimation due to the instillation. The first series of
three scans was made of the eye that had first received fluorescein.
Immediately after these scans, a series of three scans was made of the
other eye. Hereafter, the eye into which the fluorescein had first been
instilled, was measured again for a second series of three scans. This
procedure was repeated until three or four series of scans of both eyes
had been obtained (after approximately 15 minutes), or until the
apparent fluorescein concentration in tears dropped below 1000 ng/mL. A
nasal stimulus with alcohol vapor was then applied during 5 seconds.
Five minutes thereafter, measurements were continued as before,
starting with the eye into which the fluorescein had first been
instilled. The measurements were continued until the apparent
fluorescein concentration dropped below four times the autofluorescence
value or until 15 minutes had elapsed.
The first steady state tear turnover (TTO-1) was calculated from the
fluorescein decay before application of the alcohol stimulus and the
second steady state tear turnover (TTO-2) from the decay after the
stimulus. The IRL, expressed as the percentage decrease in fluorescein
concentration as the result of the stimulus, was calculated by forward
and backward extrapolation of the first and second steady state curves
(Fig. 1)
. All tests took place in the morning to avoid a bias in the
tear production caused by circadian rhythm.12
14
The eyes measured were divided into three groups: group A contained the
eyes affected with stromal herpetic keratitis, group B the healthy eyes
of the same patients, and group C the eyes of the healthy volunteers.
When a patient had two affected eyes, only the eye that had had the
most herpetic episodes was included in group A. Although both eyes of
the volunteers were measured, only the data from one randomly selected
eye were used in group C. When a subject had a TTO-1 above 25% per
minute, the data were not accepted, because the subject probably had
reflex tearing before the application of the stimulus.
Statistics
A nonparametric sample K-S test was used to check the normal
distribution of TTO-1, IRL, and TTO-2. A parametric single-factor
analysis of variance, testing the null hypothesis that the values did
not differ among the three participating groups, was performed. The
Tukey multiple comparison procedure was applied on each pair of groups
using the Kramer approximation for unequal numbers of values. The
procedures were applied to the values of TTO-1, IRL, and TTO-2. The
data from the left and the right eyes of the healthy control subjects
in our study were compared to see whether there were any differences
(Student’s t-test), and the data in the selected eyes of
these control subjects were compared to those of healthy volunteers in
a previous study,7
to see whether the groups were
comparable. A paired Student’s t-test was used to compare
the values of TTO-1 and TTO-2 in each of the three groups.
Nonparametric tests were used as a control. A single-factor analysis of
variance using the Kruskal-Wallis rank test with correction for tied
ranks was used, and the Tukey type multiple comparison test was applied
on each pair of groups with correction for tied values and unequal
numbers in the groups. The Mann-Whitney test was used for comparing two
groups.
|
Results
|
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Figure 1
shows the TTO-1, IRL, and TTO-2 curves of one eye of a
21-year-old healthy volunteer, whereas Figure 2
shows the curves of the affected eye of a 73-year-old patient with
latent herpetic keratitis. Note the difference between the first
fluorescein decay (TTO-1) in Figures 1
and 2
.
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Figure 2. As in Figure 1
, for the affected eye of a 73-year-old patient with HSV.
Note the longer measurement time in comparison with the healthy
volunteer and the slow first fluorescein decay in comparison with the
second one.
|
|
The data of the participants and the results of the measurements are
shown in Table 1
One of the healthy volunteers was not accepted because he had
giant papillary conjunctivitis. There is a discrepancy in the numbers
of healthy and affected eyes in the patients, because there was one
patient with a glass eye, one with a corneal defect in the second eye,
and one with both eyes affected. The data from all groups were normally
distributed (P > 0.41).
The TTO-1, IRL, and TTO-2 data in the left and right eyes of the
healthy control subjects in our study were not significantly different,
which indicates similar left and right eye measurements
(P = 0.47, P = 0.45, P = 0.29, respectively). There were no differences in the TTO-1, IRL, and
TTO-2 data between the randomly selected eyes of the healthy control
subjects in our study and those in the previous study,7
indicating similar measurements in both studies (P =
0.16, P = 0.35, P = 0.49,
respectively). Therefore, both groups of healthy control subjects were
taken together (one randomly selected eye per individual). Although the
average age of our eight healthy control subjects was lower than that
of the patient groups, the age among groups did not differ
significantly (P > 0.22, Table 2
).
The TTO-1 data did not differ significantly between the affected and
healthy eyes of the patients and were approximately two times lower
than those in the randomly selected eyes of the healthy control
subjects (P < 0.024, Tables 1
2
) and were almost
equal to the TTO-2 values in the healthy control subjects
(P = 0.16 and P = 0.22, respectively).
The average difference between TTO-2 and TTO-1 was approximately 0%
per minute in the eyes of the patients (P > 0.36) and
approximately 7% per minute in healthy volunteers (P < 0.00005, Table 1
, Fig. 3
). The IRL and TTO-2 were not significantly different among the three
groups (ANOVA; P > 0.5).
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Figure 3. Difference between the TTO after and before the alcohol stimulus
(TTO-2 - TTO-1) as a function of age, in each eye in the study.
|
|
|
Discussion
|
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In normal individuals, the basal tear turnover after nasal
stimulation (TTO-2) is attributed mainly to basal tears.7
In eyes of patients with latent corneal herpes, the mean TTO-1 was
similar to the mean TTO-2, which in turn did not differ from the mean
TTO-2 in healthy volunteers. It is therefore likely that mainly basal
tears caused the TTO-1 in the patients. Under normal physiological
conditions, there are probably no reflex tears in these patients, but
they can still be evoked after a strong stimulus, because the IRL in
these patients was as high as in the healthy volunteers. Therefore, we
have to assume that the HSV does not affect the tear production of the
main and accessory lacrimal glands.
It was surprising to find no significant differences in tear secretion
between the herpetic and the contralateral healthy eyes of the
patients. There are two possible explanations for the low TTO-1s in
both eyes of the patients: The tear secretion mechanism of the healthy
eye is also affected by the HSV, or the dryness is not caused by the
herpes infection but predisposes to chronic recurrences of stromal
herpes or makes the eye more sensitive to irritation from a herpetic
infection. However, it should be noted that the number of healthy and
affected eyes of the patients is low, and therefore the results may be
inaccurate.
There are arguments that support either statement. Although it is
commonly accepted that HSV causes a unilateral infection, we can assume
from our data that the herpes virus may be capable of affecting the
tear secretion mechanism of the other eye as well. Others have found
that HSV, when applied to mice, can cause central nervous system (CNS)
demyelination, whereas the peripheral nervous system (PNS) is not
damaged.21
22
23
24
This demyelination occurs in ocularly
infected mice at the trigeminal root entry zone
(TREZ).21
24
The reflex tear arc goes from the trigeminal
nerve (nerve V) in the nasal mucosa, through the TREZ, and back to the
main lacrimal gland by route of the nervus facialis and again the
nervus trigeminus.25
When nerves are demyelinated, the
transport of action potentials in the axons is blocked or
suppressed.22
26
When the patients are given a strong
alcohol stimulus, the IRL is as high as in healthy volunteers. We
hypothesize, that, as a result of the demyelination in the TREZ, the
strong alcohol stimulus is allowed through, whereas the action
potentials under normal physiological conditions are blocked. This
theory could only correspond with our data when the TREZs are
bilaterally demyelinated by the HSV infection. Bilateral demyelination
of the TREZ by HSV has been found in mice in a study in San
Francisco.21
However, this bilateral myelination was
explained by self-inoculation of the other eye with HSV by the mice. In
contrast, herpes virus is detected on the contralateral side of the
brain stem in unilaterally infected mice.27
28
Contralateral demyelination of the TREZ could therefore be caused
through cross infection by the initially infected TREZ.
The other explanation is that dryness causes irritation that enhances
stromal herpetic inflammation. If dryness is caused by HSV, it should
be located at the infected site only, and the healthy eye would have
normal tearing. However, this was not the case, because the dryness was
located in both eyes. Because patients with dry eyes produce few tears,
they may be more prone to corneal damage than patients with normal
tearing.29
Because it has been shown that even in patients
with Sjögren syndrome, the secretory IgA is similar to that in
control subjects,30
31
it is unlikely that the humoral
defense is decreased in patients with dry eye. However, previous
studies in mice have shown that corneal damage may stimulate influx of
Langerhans cells and subsequent stimulation of a cellular corneal
immune response, leading to more severe stromal
inflammation.32
In view of these findings, patients with a
combination of dry eyes and herpetic stromal infection in one eye may
have consulted our clinic more frequently than patients with normal
tear production, because their eyes are more sensitive and prone to
irritation.
The loss of corneal sensitivity in patients with herpetic keratitis may
also affect the tear mechanism. However, because the loss of corneal
sensitivity is only unilateral, it cannot explain the bilateral dryness
found in our study.
The differences between the patients with herpetic keratitis and
healthy volunteers could also be explained by the differences in age of
the three patients who had undergone corneal transplantation.
However, when only the older patients or patients who had not undergone
transplantation were selected, TTO-1, IRL, and TTO-2 did not differ
significantly.
|
Conclusions
|
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We can conclude that patients with stromal herpetic keratitis have
dry eyes. However, the tear production of the main and accessory
lacrimal glands is not affected by the HSV, so that the reflex arc for
reflex tears is still intact but not working properly under normal
physiological conditions.
|
Footnotes
|
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Submitted for publication April 11, 2001; revised July 18, 2001; accepted August 14, 2001.
Commercial relationships policy: N.
The publication costs of this article were defrayed in part by page charge payment. This article must therefore be marked "advertisement" in accordance with 18 U.S.C. 
1734 solely to indicate this fact.
Corresponding author: Martine J. Jager, Department of Ophthalmology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands; m.j.jager{at}lumc.nl.
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Abstract
Introduction
