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CE Credit Article
Clinical & Refractive Optometry is pleased to present this continuing education (CE)
article by Ashlee D. Arlien et al entitled Horner’s Pupil in Patient With Ipsilateral
Facial Pain. In order to obtain 1-hour of COPE-approved CE credit, please refer to
page 100 for complete instructions.
Horner’s Pupil in Patient
define more benign conditions. Recently, it has been With Ipsilateral Facial Pain
suggested that more accurate terminology is warrantedin order to keep Raeder’s in its original sense distinct Ashlee D. Arlien, BA; Craig M. McCormick, OD; from other entities such as cluster headaches and migraine Leonid Skorin, Jr., OD, DO, FAAO, FAOCO Neuro-imaging, laboratory tests, pharmacological ABSTRACT
The definition of Raeder’s paratrigeminal syndrome
consultation are part of the management of this clinical has generated confusion over the years. It has gone
entity. Finding the location of the lesion responsible for from being characterized by a partial Horner’s
the Horner’s syndrome is crucial in differentiating syndrome and persistent unilateral supraorbital pain
between a malignant or more benign condition.
to being designated to any painful post-ganglionic
Traditional pharmacological testing for Horner’s Horner’s syndrome. The earliest to most recent
definitions given to Raeder’s are discussed in this
syndrome as well as alternatives such as 1% apraclonidine article as are suggestions for more precise terminology
(Iopidine) and 1% phenylephrine (Neosynephrine) are that reflects the anatomy more accurately. A case is
presented of a patient with new onset Horner’s
pupil of the right eye in combination with ptosis
(Tegretol) are both anticonvulsants that have proven to be and ipsilateral facial pain. A diagnosis of Raeder’s
effective treatments for the pain associated with Raeder’s.
paratrigeminal syndrome (pericarotid sympathetic
Gabapentin is promising in that it has fewer side effects impairment not related to migraine-like recurrent
than previously prescribed carbamazepine and still offers hemicrania) was made. Pharmacologic testing with
patients relief from severe neuralgia.
1% phenylephrine was performed to confirm the
Horner’s pupil. Neuro-imaging was done to rule
out other diagnoses. New treatment modalities in
CASE REPORT
the management of pain associated with Raeder’s
Subjective
syndrome are introduced.
A 50-year-old Caucasian male presented with a headachewhich started six days earlier. The patient stated he had INTRODUCTION
extreme pain behind his right eye. This pain would wax In 1918, Raeder described a patient with a “para- and wane. The pain was concentrated to the right temple trigeminal” oculosympathetic defect characterized by a and periocular region and at the time of examination had partial Horner’s syndrome and unilateral persistent pain in improved to a dull ache. The patient denied any phono- the supraorbital region.1 Raeder’s syndrome has since phobia, photophobia, nausea, or vomiting. He also noted evolved from being an ominous, malignant diagnosis to mild blurring of the right eye. His medical history was having three different classifications including two that positive for an umbilical hernia. The patient deniedhaving migraines or cluster headaches in the past. He alsodenied any trauma. He was a non-smoker and reported A. D. Arlien — 4th-Year Optometry Student, Pacific University College of minimal alcohol intake. The only medication he was Optometry, Forest Grove, OR; C.M. McCormick — Staff Optometrist, taking was Bayer Back and Body (Aspirin 500 mg and Albert Lea Eye Clinic, Mayo Health System, Albert Lea, MN; Caffeine 32.5 mg). He was not allergic to any medications.
L. Skorin, Jr. — Staff Ophthalmic Surgeon, Albert Lea Eye Clinic,Mayo Health System, Albert Lea, MN His father had a positive history of depression, hyper- Correspondence to: Dr. Leonid Skorin Jr., Albert Lea Eye Clinic, 1206 W. tension, diabetes mellitus Type 2, and migraines; and his Front Street, Albert Lea, MN 56007; e-mail: skorin.leonid@mayo.edu sister had a history of migraines as well.
94 Clinical & Refractive Optometry 17:3, 2006
Fig. 1 Ptosis and pupil miosis in the right eye prior to pharmacological
Fig. 2 Pupil dilation and eyelid elevation in the right eye in response
to instillation of 1% phenylephrine into both eyes. Some mild dilation isalso evident in the left pupil after instillation of 1% phenylephrine.
Objective
before instillation of 1% phenylephrine to 8 mm at the end Uncorrected visual acuity was 6/6 (20/20) and 6/6-1 of testing. The left eye dilated 0.5 mm from baseline after (20/20-1) in the right and left eyes, respectively.
instillation of 1% phenylephrine (Fig. 2). The test was Confrontation visual fields were full to finger count in considered positive with the deficit located in the post- both eyes. Extraocular muscle movements showed full ganglionic (third order) neuron of the oculosympathetic range of motion without pain on movement in both eyes.
pathway. The diagnosis of Horner’s syndrome was In bright illumination, the pupils measured 4 mm in the changed to Type 3 Raeder’s paratrigeminal neuralgia of right eye and 5 mm in the left eye. In dark illumination, the pupils measured 6 mm in the right eye and 8 mm inthe left eye. No relative afferent pupillary defect was PHARMACOLOGIC EVALUATION
observed. The margin reflex distance from the top lidmargin to the pupil reflex (MRD ) and from the bottom lid margin to the pupil reflex (MRD ) was also measured in The ocular structures innervated by the sympathetic each eye. The MRD for the right eye was 1 mm compared pathway include the iris dilator and smooth muscle of to 4 mm for the left eye. The MRD for both eyes was the lids. The sympathetic pathway starts with the central 6 mm (Fig. 1). There were no visible vesicular lesions on neuron which sends its fiber from the spinal cord to a the scalp or periorbital region. Pressures with Goldmann synapse with the pre-ganglionic neuron in the cervical applanation tonometry were 18 mmHg and 20 mmHg for dorsal column. The pre-ganglionic fiber leaves the spinal the right and left eyes, respectively. Biomicroscopy and cord at the level of T-1 to T-3 and passes into the chest, courses over the apex of the lung, and loops around thesubclavicular artery to synapse in the superior cervical Assessment and Plan
ganglion.4 The post-ganglionic fibers form the carotid Horner’s syndrome of unknown etiology was diagnosed plexus around the internal carotid artery and enter the and the patient was scheduled to come back for pharma- skull via the carotid canal.4 The fibers then take multiple cological pupil testing. Magnetic resonance imaging pathways to the target structures. An interruption along (MRI), magnetic resonance angiography (MRA), carotid this pathway could result in a Horner’s syndrome with ultrasound, and chest X-ray were also ordered and all pupil miosis, lid ptosis, and anhydrosis. came back with no significant abnormalities. On his In the sympathetic pathway the neurotransmitter follow-up visit two days later, pharmacologic testing for released by the pre-ganglionic fiber is acetylcholine and the Horner’s syndrome was done. Baseline measurements the neurotransmitter released by the post-ganglionic fiber were taken and then two drops of 1% phenylephrine were is norepinephrine. Therefore, adrenergic agonists are used instilled into each eye. After ten minutes, measurements in pharmacological pupil testing and include direct-acting were repeated. The MRD for the right eye improved from norepinephrine and epinephrine, and indirect-acting 1 mm to 3 mm, while the left eye continued to be 4 mm hydroxyamphetamine and cocaine. Table I lists these throughout testing. The right pupil dilated from 6 mm Horner’s Pupil in Patient With Ipsilateral Facial Pain — Arlien et al 95
Table I Mechanisms of action of adrenergic agonists in the
Table II Dilution of commercially available phenylephrine to obtain
Direct-Acting
Concentration (%)
Desired Final
of phenylephrine
Concentration = 1%
Dilutions are prepared by mixing the number of drops of the commercially available Indirect Acting
phenylephrine (the numerator of the fraction) with the number of drops of irrigating solution or saline (the denominator).
that is released into synaptic junctionsof the iris dilator muscle the presence of norepinephrine. If the post-ganglionic pathway is compromised, the pupil will fail to dilate.
On the other hand, if the pupil dilates, this means thepost-ganglionic pathway is intact and has available Cocaine Test
norepinephrine and the lesion is either central or pre- In an intact sympathetic pathway, cocaine 10% produces ganglionic. Third order (i.e., post-ganglionic) lesions are dilation.5 If there is a disruption anywhere in the pathway, considered to be benign, while first and second-order norepinephrine is lacking in the neuromuscular junction neuron (i.e., central and pre-ganglionic) lesions are and therefore the pupil dilates poorly or not at all, resulting in a positive test. One drop should be instilled ineach eye and then another several minutes later. Because Phenylephrine Test
a compromised cornea may affect the concentration and If hydroxyamphetamine 1% is not readily available, an amount of cocaine entering the eye, procedures such as alternative is to use a weak 1% solution of phenylephrine tonometry, gonioscopy, etc. should not be performed (Neosynephrine) to demonstrate that the pupil in post- beforehand and there should be no other drops instilled ganglionic Horner’s syndrome has denervation hyper- prior to the testing. The pupils are then evaluated after sensitivity. Solutions of 1% phenylephrine do not dilate 50 to 60 minutes. Testing with cocaine is used to verify the normal pupil, but in the presence of sympathetic the presence or absence of disruption along the denervation, may produce mydriasis with the Horner’s pupil sympathetic pathway. It does not localize the lesion to any dilating more than the normal pupil.9,10 In a study of patients with Horner’s syndrome, it was found that 71% of the Recently, apraclonidine (Iopidine) 1%, an ocular patients were sensitive to 1% phenylephrine.10 hypotensive agent, has been suggested as a substitute for In our case, the patient was visiting from out of town the cocaine test.7 This is because cocaine, being a con- and was scheduled to leave shortly. A decision was made trolled substance, may be difficult to obtain. There is also to do the pharmacologic testing in one visit. The local a potential for systemic absorption and difficulty distin- pharmacy did not have cocaine, hydroxyamphetamine 1%, guishing positive and negative test results when using or apraclonidine 1% and therefore prepared a 1% solution of cocaine. Apraclonidine 1% has a weak direct action on phenylephrine. In the event where there are availability alpha 1 receptors having denervation supersensitivity and issues or time constraints, solutions of 1% phenylephrine minimal to no clinical effect on pupil dilators of normal can be made in the office. The dilution process is outlined eyes.7,8 One drop is instilled into both eyes and significant pupillary dilation occurs in the eye with Horner’ssyndrome whereas little or no dilation should occur in the MANAGEMENT AND TREATMENT OPTIONS
normal eye. Dilation of the affected pupil is seen with Appropriate patient management depends on the accurate pre-ganglionic and post-ganglionic lesions, making localization of the lesion. A central or pre-ganglionic apraclonidine 1% an alternative to cocaine that gives lesion of unknown etiology should be referred to a reliable results and is readily available.
thoracic surgeon or internist and neurologist because of Hydroxyamphetamine Test
the risk of malignancy. Post-ganglionic lesions are most If the cocaine testing is positive, the patient should be likely associated with a benign vascular headache brought back after at least 48 hours for instillation of syndrome such as Raeder’s paratrigeminal neuralgia hydroxyamphetamine (Paredrine) 1% to distinguish central which is self-limiting.5 Laboratory testing and neuro- and pre-ganglionic lesions from post-ganglionic lesions.
imaging should still be done, however, regardless of the One drop is placed in each eye and repeated one minute location of the lesion to help exclude life-threatening later. The pupils are evaluated after 30 minutes.
causes such as carotid dissection, aneurysms, and Hydroxyamphetamine 1% will cause dilation only in tumors.11 A basic chemistry profile, complete blood count 96 Clinical & Refractive Optometry 17:3, 2006
Table III Medications used in the management of pain associated with Raeder’s paratrigeminal neuralgia
Drug Category
Drug Name
Mechanism of Action
Adverse effects including
(but not limited to) the following:
reactions (aplastic anemia), skin reactions (Steven’s Johnson syndrome), and drowsiness Sedation, ataxia, weakness, fatigue, and severe withdrawal effects if not tapered off slowly polysynaptic reflexes at the spinal level, by hyperpolarization of afferent terminals Nausea, tinnitus, renal failure if decreased renal Hypersensitivity, osteoporosis, peptic ulcer disease, cataracts, hypertension, hyperglycemia, anxiety, insomnia, depression, and masking of excitability, decreased libido and appetite *Gamma-aminobutyric acid (GABA) is an inhibitory neurotransmitter in humans (CBC), erythrocyte sedimentation rate (ESR), antinuclear Treatment is usually initiated with one drug, such as antibody (ANA), and rheumatoid factor (RF) may be carbamazepine or gabapentin.13 The dose is then increased helpful in screening for inflammatory or infectious as needed and tolerated by the patient. If any single drug causes. Neuro-imaging should include MRI and MRA of proves ineffective, alternative drugs may be tried alone or the brain. A chest x-ray, specifically a lordatic view, is in combination with other medications. For instance, helpful in eliminating the possibility of a Pancoast tumor agents such as baclofen (Lioresal) may add to the effectiveness of the anticonvulsants. As with all of these Raeder’s paratrigeminal neuralgia can be very painful medications, rapid discontinuation should be avoided as and may last from hours to weeks to months before it severe withdrawal reactions may occur.
resolves spontaneously.12 In the past, several categories ofdrugs have been used for pain management. Table III lists DISCUSSION
these agents, their mechanisms, and adverse effects. The Nomenclature and Definitions
anticonvulsants have been found to be useful in treating There has been some confusion regarding the nomenclature this condition. These include carbamazepine (Tegretol), and definition of Raeder’s paratrigeminal syndrome. In phenytoin (Dilantin), oxycarbazepine (Trileptal), and 1918, Raeder1 described his first patient with a gabapentin (Neurontin). The anti-convulsants are thought “paratrigeminal” oculosympathetic defect suggesting to reduce neuralgia by decreasing the hyperactivity of the middle cranial fossa pathology. On autopsy of this patient, trigeminal nerve nucleus in the brain stem.11 Phenytoin an endothelioma was found in the middle cranial fossa.
was first introduced in 1942, and in 1962 carbamazepine By 1950, an ominous malignant aura hung over the phrase became the most commonly used drug.13 More recently, “Raeder’s syndrome” and it strongly suggested serious gabapentin has been widely used because of reduced side effects, although it is more expensive and somewhat less In 1962, Boniuk and Schlezinger1 described two subtypes of this syndrome. The first group included Horner’s Pupil in Patient With Ipsilateral Facial Pain — Arlien et al 97
Table IV Summary of earliest to most recent definitions of Raeder’s paratrigeminal syndrome
1. Horner’s syndrome plus periorbital pain 2. Horner’s syndrome, periorbital pain, and subjective Vth cranial nerve involvement 3. Horner’s syndrome, periorbital pain, subjective Vth cranial nerve, and objective signs of Vth cranial nerve involvement 4. Three categories of Raeder’s paratrigeminal syndrome • Group 1: those with either multiple parasellar cranial nerve involvement (III, IV, V, VI) or involvement of the second, third, or all three divisions • Group 2: those with a typical history of cluster headache• Group 3: those with a pain history atypical of cluster headache, in whom the first (ophthalmic) division of the trigeminal nerve only may be 5. In her book The Pupil, Irene Loewenfeld felt (1) Raeder’s syndrome in its original sense (2) cluster headaches and other migraine variants and (3) pericarotid sympathetic impairment not related to migraine-like recurrent hemicrania should be kept distinct from each other and not groupedtogether universally under Raeder’s syndrome 6. Paratrigeminal Oculosympathetic Syndrome (POSS) (Goadsby) patients with neuralgia, oculosympathetic paralysis, and variants which she feels are more benign disease processes parasellar nerve involvement as originally described by of unknown nature and self-limiting. Pericarotid conditions Raeder. In the second group, the condition occurred with pain and ipsilateral sympathetic deficits but without without parasellar involvement but was associated with migraine-like features are benign as well and differ in oculosympathetic paralysis and neuralgia. Cases that fell location from the original Raeder’s syndrome.
into the second group were felt to be more benign than With the help of modern neuro-imaging it has been suggested that the use of the term Raeder’s paratrigeminal Grimson and Thompson1 further delineated three neuralgia has become imprecise because of the careless major groups in 1980. Group I included patients with attribution of cases that do not respect the anatomy. The multiple parasellar cranial involvement or involvement of key anatomical feature necessary to understand Raeder’s any or all divisions of the trigeminal nerve. Group II syndrome is the relationship between the trigeminal nerve included those with cluster headache with an isolated and the oculopupillary sympathetic fibers. The trigeminal oculosympathetic paresis. Group III included those with nerve lies in the middle cranial fossa and in close proximity pain atypical for cluster headache with involvement of the to other cranial nerves, specifically the fibers that ophthalmic division of the trigeminal nerve. Common to innervate Müller’s muscle and the pupil dilator. Thesudomotor fibers innervating the sweat glands of the all three groups was the association of unilateral headache forehead are excluded. Therefore, a partial Horner’s with a disruption in the post-ganglionic pathway along the syndrome is a clinical sign of Raeder’s paratrigeminal syndrome. According to Goadsby,2 this brings up a Raeder made an interesting clinical observation significant argument against using the Raeder’s that pointed out the likely localization of a lesion adjacent nomenclature because conditions such as carotid disease, to the trigeminal nerve in the middle cranial fossa.
particularly carotid dissection, may give rise to pain and a According to him, it was possible to have an oculo- complete Horner’s syndrome. Also, cluster headaches may sympathetic palsy without a complete Horner’s syndrome.
lead to oculosympathetic loss and impaired sympathetic This meant that an intracranial lesion could produce all facial sweating. In both situations forehead sweating may the signs of a Horner’s syndrome except anhydrosis.
be impaired which is not consistent with Raeder’s original Since then, however, the definition of Raeder’s syndrome definition of miosis and ptosis without anhydrosis.
has encompassed other conditions such as cluster Therefore, Goadsby2 felt a more accurate term may be headaches and migraine variants producing painful paratrigeminal oculosympathetic syndrome (POSS) Horner’s syndromes. This is not consistent with Raeder’s which reflects the anatomy more precisely. Table IV summarizes the past to most current definitions of Loewenfeld3 clarifies that the pain in the original “Raeder’s syndrome” is trigeminal pain associated withdefects such as hypoesthesia, anesthesia, or dysesthesia, CONCLUSION
whereas the pain in cluster headaches or other pericarotid When a patient presents with a Horner’s syndrome, conditions occurs without impairment of the fifth nerve diagnostic pharmaceutical testing with 10% cocaine function. She then argues that Raeder’s syndrome should followed by hydroxyamphetamine has been the standard be kept distinct from cluster headaches and migraine for decades. However, in the event of availability and 98 Clinical & Refractive Optometry 17:3, 2006
time issues a 1% solution of apraclonidine or 1% Remington LA. Clinical anatomy of the visual system, phenylephrine can be used as alternatives to demonstrate 2nd Edition. St. Louis: Butterworth-Heinemann Elsevier, denervation sensitivity in the oculosympathetic pathway.
Skorin L Jr., Muchnik BG. Horner’s syndrome, Chapter 22, Dilute phenylephrine can be easily prepared in the office Neuro-ophthalmic disorders. In: Bartlett JD, Jaanus SD, eds.
Clinical ocular pharmacology, 4th edition. Massachusetts: Once the diagnosis of Raeder’s paratrigeminal Butterworth-Heinemann, 2001: 437-443.
syndrome is made, managing the patient’s severe pain Skorin L Jr., Kabat AG. Horner’s syndrome, Chapter 19, becomes the primary concern. Baclofen, naproxen, Neuro-ophthalmic disease. In: Onofrey BE, Skorin L, Jr, and amitriptyline are among those medications considered Holdeman NR, eds. Ocular therapeutics handbook: aclinical manual, 2nd edition. Philadelphia: Lippincott to be treatment options. More recently, gabapentin, an Williams & Wilkins, 2005: 550-553.
anticonvulsant, has proved to be a promising new treatment Kardon R. Are we ready to replace cocaine with for Raeder’s paratrigeminal syndrome.11,13 It has brought apraclonidine in the pharmacologic diagnosis of Horner relief with fewer side effects than its predecessor, syndrome? J Neuroophthalmol 2005; 25: 69-70.
carbamazepine, to those suffering from severe neuralgia. Morales J, et al. Ocular effects of apraclonidine in Horner’ssyndrome. Arch Ophthalmol 2000; 118: 951-954.
Finally, while there have been attempts to clarify Tantum LA. Pupil anomalies, Chapter 13. In: Onofrey BE, Raeder’s paratrigeminal syndrome, its universal application ed. Clinical optometric pharmacology and therapeutics.
has created confusion. The three classifications given to us Philadelphia: Lippincott-Raven, 1996: 1-13.
by Grimson and Thompson1 are probably the most widely 10. Ramsay DA. Dilute solutions of phenylephrine and accepted and understood definitions, but it may be time for pilocarpine in the diagnosis of disordered autonomic a more anatomically accurate and precise definition such as innervation of the iris. J Neurol Sci 1986: 73: 125-134.
11. Schechter SH. Raeder paratrigeminal syndrome.
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Goadsby PJ. “Paratrigeminal” paralysis of the oculo- www.umanitoba.ca/cranial_nerves/trigeminal_neuralgia/ pupillary sympathetic system. J Neurol Neurosurg Psych manuscript/index.html Last accessed February 6, 2006.
14. Kudrow L, Kudrow D. Cluster headache and variant Loewenfeld I. Impairment of sympathetic pathways. The syndromes. In: Cady RK, Fox AW, eds. Treating the pupil: anatomy, physiology, and clinical applications, Volume headache patient. New York: Marcel Dekker, Inc, 1995: I. Massachusetts: Butterworth-Heinemann, 1999: 1169-1177.
Horner’s Pupil in Patient With Ipsilateral Facial Pain — Arlien et al 99

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