Benign Episodic Mydriasis (Benign Episodic Pupillary Dilation)
Unequal size of pupils (anisocoria) often presents as a diagnostic challenge for clinicians because the underlying etiology may stem from a variety of factors . Anisocoria may be benign (e.g., pharmacologic dilation, tonic pupil) or may be an alarming sign of a life-threatening disorder (e.g., aneurysm, arterial dissection).
If there are no accompanying symptoms or signs (e.g., no headache, no ptosis, no diplopia or ophthalmoplegia) and the anisocoria is completely neurologically isolated it is much more likely to be benign. In addition if the anisocoria is isolated and episodic, then this anisocoria is benign and referred to as benign episodic mydriasis (BEM) . Physiologic and benign pupil asymmetry is seen in up to 20% of healthy individuals .
In contrast to physiologic anisocoria which is often asymptomatic, BEM can be noticeable to patients and physicians. BEM has been reported worldwide, with most cases affecting one eye (unilateral). Unilateral BEM is called Benign Episodic Unilateral Mydriasis (BEUM), but it can also occur bilaterally (BEBM) with either or both pupils being dilated during subsequent BEM events . The underlying etiology of BEM is not well understood; however, it has been frequently associated with an accompanying migraine in females .
The connection between BEM and migraines is ill defined. In most reports, there is an increased risk of BEM with a personal or family history of migraines as well as an increased frequency of episodes with migraine. Some reports have described BEM to be a migraine aura or an ophthalmoplegic migraine . The diagnosis of BEM however does not require concomitant migraine history.
Case reports describing BEM predominantly describe it affecting women more frequently, but it has been described in children as well with a reported age range of 5 to 53 .
The pathophysiology behind BEM is not well understood. Normal pupil size is dependent on a balance between the sympathetic and parasympathetic nervous systems controlling the iris musculature. With BEM, there may be a change in either of these two systems resulting in pupillary size imbalance. Some authors have postulated that BEM is due to decreased activity of the parasympathetic (iris sphincter), while other authors have hypothesized that an increased activity of the sympathetic nervous system (iris dilator) is the cause. While the exact mechanism remains uncertain, it is reported that there may be a greater involvement of hypoactivity of the parasympathetic nervous system that leads to BEM .
BEM has been observed to often accompany a migraine and some report it as a form of internal “ophthalmoplegic migraine”. The theory behind mydriasis in ophthalmoplegic migraine is that there is a functional exhaustion of parasympathetic fibers running within the third cranial nerve . Other authors have postulated that the cause of these episodes involves the pupillo-constrictor fibers that are concentrated over the superior arc of the 3rd cranial nerve. The posterior cerebral and the posterior communicating arteries are related to this third nerve and therefore dilate during a migraine, interrupting the pupillary fibers . Additional authors have suggested that there is a constriction of the internal carotid arteries caused by vascular edema and swelling, compressing the cranial nerves which would result in an innervational, preganglionic, parasympathetic paresis. There are other theories that go against this theory and speculate that instead of compression, it is due to ischemia that causes the association between mydriasis and ophthalmoplegic migraine . Many other mechanisms have been discussed; however, a clear etiology remains under investigation.
Patients with BEM have reported nonspecific symptoms during episodes including blurred vision, photophobia, orbital pain, and poor near response/difficulty focusing. Additional symptoms may include nausea, red eye, and diplopia . Patients typically report multiple, stereotyped, recurrent episodes of mydriasis. These episodes have been reported to last anywhere from 10 minutes to hours (but some cases are long standing for years) with a mean duration of an episode lasting 12 hours . Longer duration or more frequent episodes may be associated with the occurrence of migraines. These migraines have been observed to either have a similar time of onset or follow the episode of unilateral mydriasis . It is important to note that patients with BEM have no associated structural lesions but structural lesions can cause episodic mydriasis.
Skeik and Jabr  reported a case of BEM with a one-year history of chronic intermittent, symmetrical, throbbing, and very severe headaches that often lasted for days associated with blurry vision, nausea, vomiting, photophobia, and phonophobia. With these severe episodes, the patient experienced right eye mydriasis . Many other reports have mirrored this one with similarly associated symptoms during the time of their episodic pupillary dilation.
Although BEM predominantly occurs unilaterally, there have been rare reports where it can occur in both eyes. Ahn et al. described a 19-year-old woman with intermittent dilation of both pupils and with symptoms lasting 1-2 hours which occurred once every 2-3 days. No symptoms or abnormalities other than headaches were observed in the patient, indicating BEM . Zak described a nine-year-old girl with isolated episodic “bilateral juvenile internal ophthalmoplegia” in which both pupils were dilated, with light sensitivity and blurred distance vision. A headache accompanied the visual symptoms and there were no other symptoms .
Testing to determine if pupils are round and reactive to direct and consensual light and to near gaze, constricting, ptosis, extraocular movements, and deep tendon reflexes are analyzed, which are expected to be normal in the case of BEM . To ensure anisocoria is episodic, pupil function must be confirmed to be normal between episodes under light and in dark . Sometimes patients have taken or can be asked to take photos (“selfies”) to document the BEM and return to baseline.
Neuroimaging is not typically recommended for BEM in the absence of other accompanying symptoms or in short-term episodes when a patient presents with pupil asymmetry or symmetrical pupil enlargement . However, brain magnetic resonance imaging (MRI) and MRA may be indicated in cases of longer duration or if there is concern for something more serious (e.g., older patient, persistent anisocoria, ptosis, diplopia).
When a patient presents with pupil asymmetry, the causes can vary from severe to normal. The differential  for anisocoria includes:
- Pharmacological causes, which are the most common reason for dilated and fixed pupil
- Intracranial bleeding
- Aneurysm (superior cerebellar artery and posterior cerebral artery)
- Orbital cellulitis
- 3rd nerve palsy
- Angle closure glaucoma
- Uncal Herniation
The differential for BEM can also include diseases such as Adie’s tonic pupil, the Pourfour du Petit syndrome, and segmental spasms of the iris dilator muscle .
In cases of persistent anisocoria testing for denervation hypersensitivity to 2.5% methacholine (or 0.125% pilocarpine) and hypoactive deep tendon reflexes may confirm a tonic pupil. Typical cases of BEM do not demonstrate denervation supersensitivity however . Additionally, topical mydriatic pharmacological agents can be a cause of transient anisocoria, but a topical parasympathetic blockade can be confirmed with pilocarpine 1% . Most cases of BEM do not present during acute attacks and therefore topical testing with either pilocarpine 1/10% or 1% is generally not required.
Generally, because of its strong association with episodes of severe migraine, treatment often involves alleviating the migraine . Patients with isolated BEM have benign neurological prognosis and typical BEM does not require further neurodiagnostic studies.
Prognosis is dependent upon the etiology and careful examination of pupillary asymmetry. Although BEM itself is not life threatening, it can present similarly to a variety of other neuro-ophthalmic diseases and most cases only require reassurance.
Benign Episodic Mydriasis (BEM) is an isolated clinical finding that presents with intermittent asymmetric pupils and possible association with migraine but no other significant neurological symptoms. The prognosis of BEM is favorable; however, before diagnosing BEM, clinicians should take a thorough history and physical to rule out more pathological causes of this episodic pupil asymmetry.
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