The Wearing-Off Period of Pharmacological Dilation: An Addendum to the Management of Anisocoria
Phase: PHASE4
Conditions: Anisocoria
Sponsor: Prisma Health-Upstate

Study Title: The Wearing-Off Period of Pharmacological Dilation: An Addendum to the Management of 
Anisocoria  
NCT Number: NCT05238233  
Date: April 8, 2022 

Study Title:   The Wearing-Off Period of Pharmacological Dilation: An Addendum to the 
Management of Anisocoria 
  
Principal Investigator Name: Dr. John D. Siddens, DO 
Sub Investigator Name(s): G. Brandon Caudill, BS; Mitchell J. Wolin, MD; James H. 
Oakman, MD; William Wright, PhD  
 
Protocol Version: 2.0 
  
A. SPECIFIC AIMS 
 
According to the Section 5 - Neuro-Ophthalmology in the Basic and Clinical 
Science Course textbooks, the workup for anisocoria, or unequal pupil size, is to be 
done according to a flow-sheetappx.1. For anisocoria that is greater in bright light than dim 
light, a low-dose pilocarpine test is indicated to determine if the anisocoria is due to 
either Adie’s tonic pupil or pharmacological dilation versus third cranial nerve palsy. If 
the pupil constricts to low-dose pilocarpine, the patient is determined to have Adie’s 
tonic pupil, or parasympathetic denervation. However, if the pupil does not constrict with 
low-dose pilocarpine, a high-dose pilocarpine test is the next step in the work-up. If the 
pupil constricts to high-dose pilocarpine, the patient is determined to have a third cranial 
nerve palsy which then needs to be further evaluated with imaging including CT 
angiogram due to concern for aneurysm rupture. However, if the pupil does not constrict 
to high-dose pilocarpine, the patient likely has anisocoria due to pharmacological 
dilation. Suspected iatrogenic anisocoria does not require further evaluation with 
imaging as it should resolve as the pharmacological substance causing the dilation is 
metabolized. The flow chart in the BCSC books does not consider a phenomenon that 
may occur as the pharmacological substance causing dilation wears off. We propose 
that there is a period of time in which a pharmacologically dilated pupil may constrict to 
high-dose pilocarpine, but still appear dilated, and thus anisocoric. In this case, the 
patient would require additional imaging with CT angiogram, even though their history 
may not support any findings concerning for third nerve palsy due to aneurysm. 
Depending on the patient’s history, conducting further imaging may have greater risks 
and financial burden that are unlikely to provide valuable information. If a patient has 
history of possible pharmacological dilation in absence of aneurysm symptoms including 
headache, nausea, vision changes, loss of consciousness, then the patient should not 
be further evaluated with imaging. We aim to demonstrate the period in which a 
pharmacologically dilated eye may appear anisocoric on exam, but still respond to 1% 
pilocarpine. 
  
B. BACKGROUND AND SIGNIFICANCE 

                      
Proper workup of anisocoria that is greater in bright light is extremely important 
given the potentially dangerous causes of an inappropriately dilated pupil. Particularly, 
the reaction of the anatomically intact, inappropriately dilated pupil to 1% pilocarpine 
can be essential in distinguishing pharmacologic dilation from dilation caused by a third 
nerve palsy. Although third nerve palsies are often associated with ophthalmoplegia in 
addition to mydriasis, isolated mydriasis of the affected pupil can be seen in the early 
stages of compressive damage to the nerve.1 Whereas pharmacologic dilation is a 
benign condition that involves no further workup, compressive third nerve palsy is a 
common presenting sign of conditions such as subarachnoid hemorrhage, intracranial 
mass, intracranial aneurysm, or cavernous sinus aneurysm.1-3  
If the current algorithm is followed, any anatomically intact, yet inappropriately 
dilated eye that contracts to 1% pilocarpine, but not to 0.1%, will be considered 
suspicious for a third nerve palsy. Our proposal to clarify the “wearing-off” period of 
pharmacologic dilation will provide those utilizing this algorithm with an alternative 
etiology for a pupil that constricts to 1% pilocarpine. This addition will help to avoid 
unnecessary and expensive workup for a suspected third cranial nerve palsy. 
Currently, there is not any literature that describes the “wearing-off” period of 
pharmacological dilation as a cause of anisocoria in respect to acute clinical workup. 
Although there are examples of recent studies describing the potential use of 
constricting agents to reverse pharmacologically induced mydriasis, these studies have 
been limited in scope to symptomatic relief from the dilated eye and thus have not 
influenced the BCSC algorithm for the treatment of anisocoria in the acute setting.4 We 
believe that this study has the potential to save money and time, as well as reduce the 
stress that may be associated with consideration of a more serious diagnosis. These 
benefits will be applicable to the provider, as well as the patient, thus advancing patient-
centered high-quality care.  
 
C. PRELIMINARY STUDIES 
 
There are no preliminary studies that are pertinent to this protocol.  
 
Dr. John D. Siddens, DO is a board-certified ophthalmic plastic & reconstructive 
surgeon. He will be overseeing the project’s academic and clinical aspects. He has 
completed CITI training through Prisma Health to conduct human subjects research. 
 
G. Brandon Caudill is a fourth-year medical student who is currently in good standing to 
graduate from the University of South Carolina School of Medicine Greenville in 2022. 
He has completed CITI training through the University of South Carolina to conduct 
human subjects research. 

 
D. RESEARCH DESIGN AND METHODS AND DATA ANALYSIS 
 
Recruitment of participants for this study will be done at the University of South 
Carolina School of Medicine Greenville. We will be recruiting 15 otherwise healthy 
participants with no significant ophthalmological history. Data collection will be done at 
the Prisma Health Eye Institute - Greenville. Data analysis will be performed by Alex 
Ewing at Prisma Health. 
After participants are recruited, they will be brought into the ophthalmology clinic 
where they will first be consented for the study by a physicianappx.5. Following consent, 
participants will complete paperwork such as demographicsappx.2, contact 
informationappx.3 and exclusion/inclusion criteria formsappx.4. They will then be screened 
for hyperopia using a phoropter, have their intraocular pressures measured using a 
Reichert Tono-Pen Avia , and have their iridocorneal angle measured with a gonio lens. 
The purpose of this exam is to screen out participants with hyperopia > +1 diopter, 
iridocorneal angles where trabecular meshwork cannot be seen for greater than half of 
the angle, and/or intraocular pressures of > 22 mm Hg, as these conditions may 
increase the risk for mydriatic agent-induced angle closure glaucomaappx.4. An additional 
ophthalmic medication, proparacaine hydrochloride 0.5%, will be used to numb the eyes 
before measuring intraocular pressures and prior to gonio lens examination. This 
medication is commonly used as an ocular surface analgesic during routine eye 
examinations. This screening exam will take place at least one day prior to 
administration of any dilating drops, as examination of the angle with gonio lens may 
affect pupillary dilation through corneal contact. The initial exam will be performed by a 
physician licensed to practice ophthalmology.  
After screening, participants will be asked to return to the clinic on a scheduled 
day (within a week of screening) to have their left eye dilated.  At this visit, the diameter 
of their left pupil will be measured using a Near card in a windowless room with a set 
light-level. Tropicamide will be our agent of choice for pharmacological dilation. 
Tropicamide is widely used in ophthalmology clinics to dilate the pupil of the eye and 
has a suspected effect time of 4-8 hours of dilation.5 Participants will receive one drop 
of tropicamide in the left eye and, after the drops have had time to take effect, about 20-
30 minutes, the diameter of the participant's pupil will be measured again. After 
measurement of baseline pupillary response to tropicamide, participants will be 
dismissed and asked to return to the clinic in 3-4 hours. At this time, we will record the 
diameter of the left pupil again and compare it to the participant's baseline as well as 
post-dilation diameter. One drop of 1% pilocarpine will then be administered to the 
participant's left eye. Pilocarpine 1% is a miotic agent that is the current standard for 
workup of anisocoria of unknown cause according to the 2021-2022 Basic and Clinical 
Science Courseappx.1. After the pilocarpine has been given 10-15 minutes to take effect, 

any change in pupillary diameter will be measured. Following this measurement, 
participants will be dismissed. A positive result will be indicated by a constricting 
response of the pupil after administration of pilocarpine of > 1mm in diameter, while still 
appearing anisocoric on exam (clinically significant difference in pupillary diameter 
between right and left eyes). Application of dilating and constricting eye drops, as well 
as measurement of pupillary response will be performed by medical student volunteers. 
These volunteers will receive training on sterile eye-drop application technique as well 
as pupillary measurement using a Near card.  
In the event that no response to 1% pilocarpine is observed at the initial post-
dilation visit, or if pupillary diameter has returned to baseline prior to the administration 
of 1% pilocarpine at any point, we will ask this participant to return to the clinic on 
another day to have the process repeated in their right eye, with the modification of 
either shortening or lengthening the interval of reassessment based on their left eye’s 
response to the drops. This is to avoid any confounding from the administration of 
subsequent pilocarpine eye drops in the same eye. If the left pupil returned to baseline 
pupillary diameter prior to the 3-4 hour reassessment, we will have them return 2-3 
hours following dilation of their right eye to have their pupillary diameter checked and 
the administration of Pilocarpine 1% repeated. If the left pupil remained dilated with no 
response to 1% pilocarpine at 3-4 hours, we will have them return 4-5 hours following 
dilation of their right eye to have their pupillary diameter checked and the administration 
of Pilocarpine 1% repeated. Repeating the protocol with varied assessment times in the 
contralateral eye will be in an effort to compensate for expected variation in each 
participant’s response to tropicamide and 1% pilocarpine. Despite this, it is possible that 
we will not be able to capture this critical window in each participant, if one exists. 
However, we do not believe it will be necessary to demonstrate the phenomenon in all 
participants, and a minimum of 2 positive results should be sufficient to demonstrate our 
proposed concept for this preliminary study.  
 
E. PROTECTION OF HUMAN SUBJECTS 
1.  TARGET POPULATION: 
 
We plan to conduct the study with 15 medical student volunteers at the University 
of South Carolina Greenville. Exclusion criteria include a history of angle closure 
glaucoma, any other type of glaucoma, or any elevated eye pressure readings as well 
as any history of intraocular surgery or procedure. Exclusion will also occur if the 
participant is found to be hyperopic to >+1 diopter, has an intraocular pressure of > 22 
mm Hg in either eye, or displays an iridocorneal angle where trabecular meshwork 
cannot be seen for greater than half of the angle in either eye, as these features are 
known to increase the risk of angle closure glaucoma when using dilating eye drops. 

Finally, those with a known allergy to natural rubber latex will be excluded from the 
study. 
We chose a sample size of 15, as this is a proof of concept, and thus we would 
like to demonstrate a minimum of 2 instances of pharmacologically dilated eyes that 
constrict > 1mm to 1% pilocarpine. We feel that at least 15 participants will be 
necessary to guarantee that we witness at least 2 instances of the proposed 
phenomenon, assuming that we test both of their eyes independently with varying 
timeframes of reassessment. If we limited the study to < 15, we may not be able to 
witness the desired effect without subjecting participants to multiple rounds of testing.  
If we are able to describe a period in which the pharmacologically dilated pupil 
responds to 1% pilocarpine with >1mm of constriction but maintains the appearance of 
anisocoria that is worse in bright light in two or more participants, this study will serve as 
a pilot study to demonstrate the need for further research on the concept in order to 
make an addendum to the current treatment algorithm for anisocoria.  
      
2.  RECRUITMENT PLANS: 
 
Recruitment of subjects will be done in person at the University of South Carolina 
School of Medicine Greenville, via the school newsletter that is sent to the student body 
on a weekly basis, and with email correspondence via the Ophthalmology interest group 
at the school. Approval has been obtained from school administration to conduct 
recruitment onsite and via electronic correspondenceappx.6,7. 
 
3. EXISTING DATA/SAMPLES: 
 
     There are not any existing data or samples for this study. 
  
4.  CONSENT/ASSENT: 
 
The participants will be asked to sign a consent form prior to participationappx.5.  
The study doctor will consent the participants before any study procedures are 
completed. All communication will take place in a private setting.  The participant will be 
given ample time to read the consent and have all questions answered prior to providing 
signature.  The consent will be signed and dated by all parties and a copy will be 
provided to the participants at the time of consent. The consent will discuss risks of eye 
dilation including blurred vision for several hours following drop administration. 
Participants will also be informed of the risk of angle-closure glaucoma, and will be 
screened for any significant ophthalmological history, which will exclude them from the 
study. Participants will have ample opportunity to ask any questions concerning what to 
expect from and potential risks of dilating drops.  
 

5.  POTENTIAL RISKS: 
 
Drug Tropicamide: 
The risks of the study are largely limited to side effects from the dilating drops, which 
are mild (increased heart rate, headache, nausea, vomiting, dry mouth, allergic 
reactions, tense muscles, stinging of eyes (transient), eye surface injury) other than the 
rare, but serious, risk of inducing angle closure glaucoma.  Participants will be 
instructed to monitor symptoms of angle closure glaucoma including headache, nausea, 
and eye pain, and participants with history of angle closure or any other type of 
glaucoma will be excluded from the study.   
Drug Pilocarpine:  
 
A possible side effect is retinal detachment, an emergency situation in which a thin layer 
of tissue (the retina) at the back of the eye pulls away from its normal position. This side 
effect is serious but extremely rare. Other side effects, which are less severe, but may 
occur more frequently include: brow ache, headache, blurred vision, eye irritation, eye 
pain, watery eyes and visual impairment (including dim, dark, or jumping vision). 
 
Drug Proparacaine Hydrochloride: 
 
Occasional temporary stinging, burning and conjunctival redness may occur with the 
use of proparacaine. A rare, severe, immediate-type, apparently hyperallergic corneal 
reaction characterized by acute, intense and diffuse epithelial keratitis, a gray, ground 
glass appearance, sloughing of large areas of necrotic epithelium, corneal filaments and 
Sometimes iritis with descemetitis has also been reported. 
 
Therefore, the small likelihood of risks outweighs the benefit of improving understanding 
of the time parameters of the pharmacological effects of dilation drops. The participants 
will likely experience blurred vision, particularly near vision, for up to eight hours after 
administration of dilating drops. The participants will be asked to use dark sunglasses 
when in bright sunlight or when driving for at least twelve hours.  
For precautionary measures, participants will be asked to contact the clinic if vision is 
moderately or severely blurred following the administration of Tropicamide, or if they 
experience any symptoms of acute angle closure glaucoma or retinal detachment.  If 
angle-closure glaucoma or retinal detachment are suspected, we plan to adhere to 
standardized protocol for treatment. 
 
Devices: 

There is a small risk of corneal abrasion with handheld applanation tonometry and 
gonioscopy, as in both cases direct contact is made with the cornea. This is extremely 
rare, and we are mitigating this risk by having a trained physician (Dr. Oakman) perform 
these exams. These are both examination techniques used in the eye office daily. 
 
The Reichert Tono-Pen Avia uses tips that contain natural rubber latex which may 
cause allergic reactions. Participants will be screened for a known allergy to natural 
rubber latex and will be asked to monitor for signs and symptoms of an allergic reaction 
following use of the Tono-Pen. 
 
6.  POTENTIAL BENEFITS: 
 
This research study is not expected to directly benefit individual subjects but is 
likely to yield generalizable knowledge which contributes to the field.  The information 
gained from this study may be useful and may help others who will be undergoing 
evaluations for anisocoria in the future.   
  
7.  CONFIDENTIALITY 
 
Information obtained about participants during this research may be published, 
but they will not be identified. Information that is obtained concerning this research that 
can be identified will remain confidential to the extent possible within State and Federal 
law. The investigators associated with this study, the sponsor, and the Institutional 
Review Board will have access to identifying information. All records in South Carolina 
are subject to subpoena by a court of law. Study information will be securely stored in 
locked files and on password-protected network storage.   
 
8. COMPENSATION: 
 
We plan to provide participants with a gift card (Clincard) for their time spent 
conducting the study. We plan to request $50 per participant. Potential medical student 
participants will be advised that their participation in the study will in no way affect their 
grades, evaluations or medical school standings.  
 
9.  WITHDRAWAL: 
 
Participants may withdraw at any point, but the gift card will not be given as 
compensation unless participants complete the entire study. If participants fail to meet 
all inclusion criteria or meet any exclusion criteria during their initial visit and screening 
exam, they will not be able to proceed with the experiment and therefore will not receive 
compensation. 
  

F. REFERENCES/LITERATURE CITATIONS 
 
1. Biousse V, Newman NJ. Third nerve palsies. Semin Neurol. 2000;20(1):55-74. 
doi: 10.1055/s-2000-6833. PMID: 10874777. 
 
2. Eyster, E. F. “Oculomotor Palsy from Minor Head Trauma. An Initial Sign of 
Basal Intracranial Tumor.” JAMA: The Journal of the American Medical 
Association 220, no. 8 (May 22, 1972): 1083–86. 
https://doi.org/10.1001/jama.220.8.1083. 
 
3. Levy, J., Marcus, M., Shelef, I. et al. Acute angle-closure glaucoma and pupil-
involving complete third nerve palsy as presenting signs of thrombosed 
cavernous sinus aneurysm. Eye 18, 325–328 (2004). 
https://doi.org/10.1038/sj.eye.6700625 
 
4. Karpecki, Paul M., Shane A. Foster, Stephen M. Montaquila, Shane R. Kannarr, 
Charles B. Slonim, Alan R. Meyer, Mina P. Sooch, et al. “Phentolamine Eye 
Drops Reverse Pharmacologically Induced Mydriasis in a Randomized Phase 2b 
Trial.” Optometry and Vision Science 98, no. 3 (March 2021): 234–42. 
https://doi.org/10.1097/OPX.0000000000001656. 
 
5. Hong D, Tripathy K. Tropicamide. [Updated 2021 Jul 25]. In: StatPearls [Internet]. 
Treasure Island (FL): StatPearls Publishing; 2021 Jan-. Available from: 
https://www.ncbi.nlm.nih.gov/books/NBK541069/ 
 
 
  
G. APPENDIX 
 
See Attached (Appx1-7)