Should “Retro-ocular Pain, Photophobia and Visual Acuity Loss” Be Recognised as a Distinct Entity? The ROPPVAL Syndrome

ABSTRACT

Unilateral retro-ocular pain, photophobia and visual disturbance in patients suspected as having acute optic neuritis was described as a distinct clinical entity by Jefferis et al. in 2018. We hereby report a further four patients with the same clinical phenotype and propose the term ROPPVAL syndrome (Retro-Ocular Pain, Photophobia and Visual Acuity Loss). All of them had a previous (mis)diagnosis of optic neuritis. All of the patients had normal ocular and neurological examinations, no relative afferent pupillary defect and no objective structural abnormality was identified. We also discuss possible mechanisms, the role of cycloplegics that we found to be useful in reducing symptoms, and the importance of distinguishing this syndrome from optic neuritis

Introduction

Optic neuritis (ON) is a common cause of visual loss in the young patient. In fact, patients with eye pain and ipsilateral visual loss are frequently referred to Neuro-ophthalmology clinics with a possible diagnosis of ON. Jefferis et al. in 2018 reported a case series of six patients affected by unilateral visual loss, retro-ocular pain and ipsilateral photophobia in whom no structural or objective abnormalities were not found.¹ Their patients were referred as having possible acute unilateral optic neuritis but clinical examination, neuroimaging, electrodiagnostic testing, optical coherence tomography (OCT) scans (macula and optic nerve) and clinical examination failed to provide an explanation for the patients’ symptoms and signs. They proposed that this is a migraine syndrome and that the decreased visual acuity is a functional consequence of the pain and photophobia. After their paper, we collected a case series of four patients (Table 1) who fulfilled the following criteria:

1. Retro-ocular pain with visual acuity loss not explained otherwise

2. Unilateral and ipsilateral photophobia (usually the main complaint)

3. No relative afferent pupillary defect (RAPD) in the affected eye

4. No evidence of ON, multiple sclerosis (MS), or other eye, sinus or neurological diseases responsible for their complaints

5. Normal contrast-enhanced brain and orbit magnetic resonance imaging (MRI)

Table 1.

Symptoms and examination findings

Pt	Sex	Age	Eye	Previous or current medication	PPVAL	ONSS	Brain MRI	History of migraine	Previous diagnosis	Quality of pain	Time course of pain	BCVA in affected eye on presentation	Final BCVA	Ishihara test presentation – final visit	RAPD	Therapy	Improvement with cycloplegic drops
1	F	18	OD	None	Yes	None	Normal	No	Retrobulbar ON	Throbbing	6–8 hours per day, 2–4 days per week	6/18	6/6	5/12 – 12/12	No	amitriptyline	Not given
2	M	25	OD	None	Yes	Nausea	Normal	Yes	Retrobulbar ON	Throbbing	12 hours, 1–2 days per week	6/36	6/6	2/12 – 12/12	No	amitriptyline	Not given
3	F	19	OS	NSAIDs	Yes	Malaise and headache	Normal	No	Retrobulbar ON	Throbbing	1–2 hours, 1 day per week	6/9	6/6	5/12 – 12/12	No	NSAIDs	Yes
4	F	45	OD	NSAIDs	Yes	None	Normal	NO	Retrobulbar ON	Sharp	Constant, 2–5 days per week	CF	6/6	TP – 12/12	No	NSAIDs	Yes

BCVA = Best corrected visual acuity; MRI = Magnetic resonance imaging; NSAIDs = Non-steroidal anti-inflammatory drugs, OD = Right eye; ON = Optic neuritis; ONSS = Other neurological or systemic symptoms; OS = Left eye; PPVAL = Photophobia, pain and visual acuity loss; Pt = Patient; RAPD = relative afferent pupil defect; TP = Test plate.

We agree with Jefferis et al. that this is a distinct clinical syndrome for which we propose the term “ROPPVAL” syndrome (Retro-Ocular Pain, Photophobia and Visual Acuity Loss). Our patients, as theirs, experienced episodes of unilateral retro-ocular pain, ipsilateral photophobia and various degrees of visual loss but with a stereotyped presentation in which photophobia was the striking symptom. We also found a possible therapeutic (and diagnostic?) role of cycloplegia since in two patients in whom cyclopentolate drops were instilled to test refraction the pain and photophobia were relieved. Interestingly, visual acuity was unaffected by cycloplegia and improved only after pain management. Patients with ROPPVAL syndrome are often misdiagnosed as having ON. Clinicians should be aware of this recently described syndrome.

Case reports

Case 1

An 18-year-old woman presented with retro-ocular pain, not exacerbated by eye movements and visual loss in her right eye (OD). Her main complaint, however, was marked unilateral and ipsilateral photophobia. She began to experience these symptoms two years previously. The pain was throbbing, usually lasted about 6–8 hours per day and continued for 2–4 days. She denied other symptoms typical of migraine and was under no medication. During her first attack a putative diagnosis of retro-bulbar ON was made. She underwent contrast-enhanced brain and orbit magnetic resonance imaging (MRI), which was unremarkable, and a lumbar puncture was negative for oligoclonal bands. Intravenous steroids were given but no clinical improvement was reported. Notably, her symptoms gradually resolved over the following 3 months. During the current attack, her best-corrected visual acuity (BCVA) was 6/18 OD and 6/6 in the left eye (OS). Her pupils were equal and briskly reactive to light with no RAPD. Slit lamp examination (SLE) was completely normal in both eyes (OU) as well as fundus examination. Amitriptyline 50 mg/day was prescribed with resolution of her symptoms in two weeks. Thus, she was diagnosed with ROPPVAL syndrome and reassured that there was no evidence of MS.

Case 2

A 25-year-old man presented to the emergency complaining of a one day history of marked photophobia, retro-ocular pain and blurred vision OD associated with mild nausea. He reported a previous history of classical migraine when he was a teenager with the last attack occurring 7 years previously. A neurological examination was unremarkable and a brain computerised tomography (CT) scan was normal. Retro-bulbar ON was suspected by the neurologist who scheduled the patient for contrast-enhanced brain MRI. On examination in our department his BCVA was 6/36 OD and 6/6 OS. Both SLE of the anterior segments as well as his fundi were normal. His pupils were equal and briskly reactive to light with no RAPD and there were no other signs of ON. His MRI was later reported as normal with no signs of optic nerve enhancement or other features suggestive of MS. On repeated history, the patient reported that in 2018 he experienced a six month period of recurring throbbing unilateral retro-ocular pain and marked ipsilateral photophobia with a variable degree of “visual blurring”. He specifically reported these episodes were different to his previous migraine attacks. A final diagnosis of ROPPVAL syndrome was made and his symptoms disappeared in one month on amitriptyline 30 mg/day.

Case 3

A 19-year-old woman presented complaining of a 2-day history of intense photophobia, retro-ocular pain and blurred vision OS. She also reported a throbbing headache and malaise. She had been experiencing one or two attacks per year of this from the age of 17, with resolution or improvement with ibuprofen and/or paracetamol. Each attack lasted one or two hours, typically occurred once per week. Her family history was positive for a diagnosis of Chiari type II malformation in her sister. She denied a previous history of migraine and previous contrast-enhanced brain MRI was negative for ON or a Chiari malformation. At this presentation, a neurological examination and CT scan of her brain were both normal was normal. A possible diagnosis of retro-bulbar ON was made and she was scheduled for a contrast-enhanced brain MRI. On examination in our department BCVA was 6/6 OD and 6/9 OS. Both anterior segment and fundus examinations were normal. Her pupils were equal and briskly reactive to light with no RAPD and no other signs of ON. In order to complete her BCVA examination, refraction OU was made after 1% cyclopentolate drops were instilled twice. Interestingly, the photophobia and retro-ocular pain showed a great improvement despite her visual acuity remained reduced. The MRI was unremarkable, thus a diagnosis of ROPPVAL syndrome was made. She continued to take NSAIDs to control her attacks but refused cycloplegic drops because of blurred vision at near. After two weeks her symptoms had completely resolved.

Case 4

A 45-year-old woman presented with a 1 week history of complaining of photophobia, sharp retro-ocular pain and visual loss OD. Her history was positive for recurrent attacks of photophobia and eye pain in the same eye (constant, lasting 2–5 days per week, three to four episodes per year). She had a previous diagnosis of retro-bulbar ON at age 35 for which she was given intravenous steroids. She could not remember whether her previous treatment with intravenous steroids was effective and no previous reports were available except for an MRI. Each time she experienced pain and severe photophobia she used to take paracetamol with some improvement. On examination in our department her BCVA was counting fingers OD and 6/6 OS. SLE was unremarkable as was the fundus examination. Assessment for an RAPD was difficult and unpleasant due to the severe photophobia in the affected eye, but was finally excluded. An OCT scan of the macula and optic nerve (peripapillary retinal nerve fibre layer) was normal and visual evoked potentials (VEPs) were also within normal limits. These findings pointed against her previous diagnosis of ON and when her previous MRI was re-evaluated no signs of ON were detected. After the experience with case 3 1% cyclopentolate drops were administered twice with a marked improvement in both pain and photophobia. He refraction was negative for hyperopia or other ametropias. Paracetamol was given with resolution of her symptoms in a few days. Notably, she requested 1% cyclopentolate drops to improve the pain and photophobia for any subsequent attacks she might have. She was diagnosed with ROPPVAL syndrome and reassured that there was no evidence of MS.

Discussion

In this series, we present four cases of Retro-Ocular Pain, Photophobia and Visual Acuity Loss (ROPPVAL) as part of a unique stereotypical syndrome. Our cases complained of unilateral visual loss and retro-ocular pain, but in none did the pain get worse with eye movement, as frequently happens in ON. Notably, the main visual complaint was photophobia (always unilateral and ipsilateral), which is not a symptom of ON in which, indeed, light sensitivity is decreased.²

In none of our patients were there any signs of recurrent epithelial erosions of the cornea (REEC), which could have been another cause of both pain and photophobia. In contrast to REEC, patients affected by ROPPVAL do not manifest tearing, red eye and do not have a history of previous traumatic injury of the cornea. Moreover, none of our patients reported signs or symptoms of cluster headache, another syndrome able to cause pain and photophobia, or classical migraine. Thus, ROPPVAL seems to be a distinct clinical entity with its own pathogenic mechanism (Table 2).

Table 2.

Differential diagnosis of ROPPVAL syndrome

	ROPPVAL	REEC	CLUSTER HEADACHE	SUNA/SUNCT	CLASSICAL MIGRAINE	TYPICAL OPTIC NEURITIS	ANTERIOR UVEITIS
Age (years)	< 45 (mean 25)	Any	20–40	>45	<40 at onset	Young	Any
Sex	F > M	Any	M > F	M > F	F > M	F > M	F = M
Laterality	Unilateral	Often unilateral	unilateral	Unilateral	Unilateral	Unilateral	Uni- or bilateral
Onset	Acute	Acute	Acute	Acute	Variable	Acute	Acute
History of corneal trauma	No	Yes (often)	No	No	No	No	No
Visual Loss	Yes (variable)	Possible	No	No	No	Yes	Variable
Retro-Ocular Pain	Yes	No	yes	In SUNCT		Yes	Possible
Retro-Ocular Pain exacerbated by eye movement	No	Possible (related to cornea)	No	No	No	Yes	No
Eye pain relieved by local anesthetics	No	Yes	Yes	No	No	No	No
RAPD	No	No	no	Possible miosis	No	Yes	No
Headache	Possible	Rare	Yes	Yes	Yes	Possible	Possible
Systemic Symptoms	Possible	No	Possible	In SUNA	Yes	No (except for symptoms of MS)	Rare (e.g. if IOP is markedly elevated etc.)
Photophobia	Yes (unilateral and ipsilateral)	Yes	Possible	Possible	Possible (bilateral)	No	Yes
Tearing	No	Yes	Yes (possible)	In SUNCT	No	No	No
Visual Aura	No	No	Rare	No	Yes	No	No
Dischromatopsia	Yes (variable)	Rare	No	No	No	Yes	Rare
Nasal Discharge	No	Yes	Possible	Possible	No	No	No
SLE	Normal	Abnormal	Normal (except tearing)	Tearing and conjunctival injection	Normal	Normal	Abnormal
Fundus Findings	Normal	Normal	Normsal	Normal	Normal	Normal	Normal
Neuro-Imaging	Normal	Normal	Normal	Normal	Normal	Abnormal	Normal
Known/proposed mechanism and pathophysiology	Unknown (possible migraine like syndrome)	Abnormal corneal epithelial growth (often after trauma)	Hypotalamus related (sleep role in the disease?)	Part of trigeminal autonomic cephalalgias	Primarily a neurogenic process with secondary changes in cerebral perfusion	Demyelinating (MS most frequent)	Variable (infectious/inflammatory, traumatic, lens related, etc)
Treatment	Systemic (as per migraine) ± cycloplegics	Local	Systemic	Systemic	Systemic	Systemic (IV steroids)	Local/systemic
Prognosis	Good	Usually good	Long-standing disease	Long-standing disease	Long-standing disease	Good – prognosis specific to MS	good

F = Female; IOP = intraocular pressure; IV = intravenous; M = Male; MS = Multiple sclerosis; RAPD = Relative afferent pupil defect; REEC = Recurrent epithelial erosion of the cornea; SUNA = Short-lasting unilateral neuralgiform headache with autonomic symptoms; SUNCT = Short-lasting neuralgiform headache attacks with conjunctival injection and tearing.

To the best of our knowledge, there is only one series by Jefferis et al. in 2018 reporting similar clinical findings.¹ The authors presented six patients with unilateral retro-ocular pain, photophobia and visual disturbance, a triad of symptoms partially or totally improved after administration of migraine drugs, thus supporting the hypotheses it may represent a subtype of migraine.

Notably, like Jefferis et al., we report a good clinical outcome when amitriptyline was given as therapeutic agent (case 1 and 2). More interestingly, both pain and photophobia also resolved when cyclopentolate eye-drops were instilled to test manifest refraction (case 3 and 4), suggesting a complex pathogenic mechanism in which different central nervous system (CNS) areas may participate.

In accordance with Jefferis et al. we support the hypothesis of ROPPVAL syndrome being a subtype of migraine with its own specific clinical features, which must be differentiated from common migraine and the more rare and still debated retinal migraine.

Migraine is a common type of headache and the third highest cause of disability in young people.³ One-third of patients suffering of classical migraine may experience visual symptoms (visual aura) like “dark holes” in the visual field (negative scotoma) or bright scintillating positive scotoma before the occurrence of the headache.⁴ Moreover, headache may also accompany the visual aura,⁵ thus pain and visual symptoms may coexist during each attack. As the visual symptoms often involve central vision then visual acuity can be expected to decrease. Importantly, in classical migraine with visual aura, symptoms are reported as binocular and homonymous suggesting their cortical origin. Conversely, in ROPPVAL syndrome patients experience unilateral and generalised vision loss with reduced BCVA, thus resembling (and for this reason often misdiagnosed as) ON, and not a blind spot or a scintillating scotoma like in migraine.

ROPPVAL syndrome should be differentiated from the rare and still debated retinal migraine, in which the vision loss is unilateral, visual symptoms spread gradually over at least 5 minutes, last between 5 and 60 minutes and are accompanied or followed within 60 minutes by headache.⁶ Such temporal evolution of the clinical picture has not been reported in our patients. It is important to outline how photophobia represents the major complaint for both our and Jefferis case series. As already stated, our patients reported severe and unilateral photophobia, ipsilateral to the visual loss, which has to be differentiated by the generic and binocular light intolerance of migraineurs. On this basis, Jefferis et al. suggested (and we agree with them) that the intense unilateral photophobia may even be the cause of the patient-reported vision loss as photophobia is known to accompany non-organic visual loss.^1,7

As previously mentioned, the ROPPVAL symptoms in our patients resolved after amitriptyline or cyclopentolate 1% drops were given. In order to explain these findings, attention should be pointed to the different CNS areas and neuronal connections involved in migraine and photophobia pathophysiology, namely, the cortex,⁸ thalamus,⁹ hypothalamus,¹⁰ cervical nerves¹¹ and, importantly and more recently, the trigeminal nerves.¹²

The trigeminal nerves provide sensing innervation to the eyes transmitting, among other things, pain sensation from the eye to the cortex. Ocular pain-sensing nerves originate in the trigeminal ganglia and reach the eye via the ophthalmic and the naso-ciliary nerves, passing through the ciliary ganglia, in which second-order parasympathetic neurons to the ciliary muscles of the eye originate, and finally reaching the globes through the short ciliary nerves. Therefore, the ciliary ganglia and the short ciliary nerves represent the final pathway for either the pain-sensing trigeminal nerves and the parasympathetic fibres to the eyes.

Photophobia is defined as a painful sensation to light exposure. Recently, a novel population of retinal neurons, intrinsically photosensitive retinal ganglion cells (IPRGCs), have been identified as photophobia transducers in the eye.¹³ Notably, these IPRGCs project onto trigeminal neurons¹⁴ and pain nuclei in the thalamus,^15,16 which are also involved in migraine pathogenesis. We believe that “stimuli”, like those involved in migraine, may trigger the trigeminal nerve fibres which collect painful light sensations from the eye when activated by IPRGCs. We believe that the ciliary ganglia located in orbital-fat behind the globe may play a major role in determining this stereotyped syndrome, because of the relief of symptoms when amitriptyline or cyclopentolate drops are administered. We can speculate that activated trigeminal pain-sensing fibres and light-activated fibres may affect parasympathetic neurons and/or vice versa. Cyclopentolate is an anticholinergic drug, thus paralyses the iris sphincter constrictor and ciliary body muscles. Cycloplegia is commonly used in ophthalmology to reduce inflammation and pain due to different ocular conditions such as iritis where the ciliary body over-contraction is the main cause of pain.

Notably, the discovery that meninges have parasympathetic innervation together with the potential of acetylcholine (Ach) receptor agonists like carbachol to trigger headaches, highlights the prominent role of cholinergic regulation in nociception in general in and primary headaches.

In 2017 Shelukhina et al. found an increase in nociceptive firing recorded by suction electrodes in peripheral terminal of meningeal trigeminal nerves of rats after administration of Ach and Ach receptor agonists. Moreover, nociceptive firing induced by carbachol was reduced by atropine. Interestingly, carbachol but not nicotine caused a massive degranulation of meningeal mast cells releasing multiple pro-nociceptive mediators. The authors concluded that “trigeminal nerve terminals in meninges, as well as dural mast cells and trigeminal ganglion neurons express a reservoir of pro-nociceptive nicotinic and muscarinic Ach receptors, which are activated by Ach released from parasympathetic nerves. These receptors represent a potential target for novel therapeutic interventions in trigeminal pain and probably in migraine”.¹⁷ The exact mechanism(s) by which cycloplegia may reduce pain and photophobia in ROPPVAL syndrome has still to be understood but we may speculate that induction of cycloplegia may interrupt a vicious cycle in which the trigeminal nerve could play a role through the ciliary muscle.

The relationship between migraine and refractive errors, with a possible role played by the ciliary muscle, has been object of studies and theories since the beginning of the 20^th century. Conflicting results have emerged from studies. Kivanc et al. found that the cycloplegic spherical equivalents values of migrainous patients with aura were lower than controls (non-migrainous) patients.¹⁸ However, they only evaluated patients with uncorrected 20/20 vision. However, Gunes et al. found that migraine patients have higher degrees of astigmatism, spherical equivalent and anisometropia than controls.¹⁹ Refractive error is mainly the result of axial length, corneal and lens power, but activity of the ciliary muscle also plays a role. Although we did not find significant ametropias (case 3 and 4), a possible role of the ciliary muscle cannot be excluded since its block with cyclopentolate was able to relieve both pain and photophobia.

We cannot explain why visual acuity did not improve after cycloplegia as happened for the photophobia, since the visual acuity loss could be a functional result of photophobia (and pain) in ROPPVAL syndrome as stated by Jefferis et al.¹ Moreover, it is also possible that different neuronal circuits may be involved, like the cortex, as part of the large migraine spectrum.

The clinical importance of recognising this new syndrome cannot be overemphasised. In 2018 Stunkel et al. published a retrospective clinic-based cross-sectional study of 122 patients referred with acute ON to a university-based Neuro-ophthalmology clinic in the United States. Astonishingly, about 60% of patients referred as ON had an alternative diagnosis, the most common being headache and eye pain, functional visual loss, and other optic neuropathies, particularly non-arteritic anterior ischaemic optic neuropathy. A correct diagnosis of ON, or alternatively its exclusion, is important also in order to avoid unnecessary investigations and treatments. Stunkel et al. reported that in patients with alternative diagnoses, 12 (16%) had received a lumbar puncture, and eight (11%) had received unnecessary treatment with intravenous steroids.²⁰

Conclusion

It is the authors’ opinion that ROPPVAL syndrome should be listed in the differential diagnosis of ON, in order to avoid unnecessary testing and psychological stress for the patient. The diagnosis to a degree is one of exclusion, but the prognosis is good and patients can be reassured about the benign nature of their problem. Photophobia is a key point in the diagnosis of this syndrome, and should alert the clinician about a possible (mis)diagnosis of ON. The clinician should remember that photophobia is unilateral and ipsilateral to the visual loss. We suggest treating these cases with non-steroidal anti-inflammatory drugs or amitriptyline and, acutely, with cycloplegics. The exact nature of this syndrome is not completely understood, but is probably a migrainous syndrome mostly confined to the eye with some role played by the trigeminal nerve. Further studies and a consistent number of cases are needed to better understand its nature and the most appropriate treatment.