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Show ORIGINAL CONTRIBUTION Horner Syndrome Associated With Ipsilateral Facial and Extremity Anhydrosis Alberto Galvez, MD, Nadim Ailouti, MD, Agusti Toll, MD, Josep Maria Espadaler, MD, PhD, and Jaume Roquer, MD, PhD Abstract: We report a patient with Horner syndrome together with anhidrosis affecting the ipsilateral face and extremities confirmed with starch-iodine and sympathetic skin response testing. No anatomic lesion was apparent. This is the first reported case in which Horner syndrome has been associated with such extensive hemibody sympathetic dysfunction in the absence of other neurologic findings. We propose a developmental disorder of neural crest migration as the cause. (J Neuro-Ophthalmol 2008;28:178-181) A variety of focal eponymic dysautonomias have an association with Horner syndrome, including harle-quin, Holmes-Adie, and Ross syndromes. The harlequin syndrome consists of unilateral facial anhidrosis and reduced facial flushing in the absence of Horner syndrome (1,2). It derives its name from the fact that under circum-stances that would provoke sweating, the affected side of the face appears pale and the other side of the face appears red (the "harlequin sign") (3). Horner syndrome consists of unilateral ptosis and miosis with or without ipsilateral facial anhidrosis. The Holmes-Adie syndrome consists of tonic pupils and reduced deep tendon reflexes. The Ross syndrome consists of the harlequin syndrome together with the Holmes-Adie syndrome (segmental anhidrosis, tonic pupils, and hyporeflexia) (2,4). Given the considerable overlap in these focal dysautonomic syndromes, there is probably a spectrum with differing mixtures of clinical manifestations (2). We report another overlap syndrome in a patient with unilateral Horner syndrome, ipsilateral facial anhidrosis, and ipsilat-eral extremity sympathetic dysautonomia confirmed with autonomic testing. We believe this to be the first reported case of Horner syndrome associated with such extensive dysautonomia. CASE REPORT Clinical Features A 35-year-old man reported a 6-year history of episodes of flushing and sweating limited to the right hemibody after vigorous exercise such as running. He had earlier noted that his right pupil was larger than his left pupil. He denied any visual symptoms and was unaware of ptosis. Ophthalmologic examination revealed a visual acuity of 20/20 in both eyes. External examination disclosed 1 mm of left upper lid ptosis with normal levator function. The right pupil measured 6.5 mm and the left pupil 4.5 mm in dim illumination. The right pupil measured 4.5 mm and the left pupil 4 mm in bright light and with near stimuli. There were no features of tonic pupil. Results for the rest of the ophthalmic examination were normal. The neurologic examination was normal with the exception of a generalized hyporeflexia (all deep tendon reflexes were diminished to 11). There were no sensory abnormalities and no postural hypotension. Results of brain and cervical-thoracic MRI were normal. Autonomic Study Results Topical Ocular Apraclonidine Test Fifteen minutes after instillation of 2 drops of 0.5% apraclonidine into each eye, the right pupil measured 3.5 mm and the left pupil measured 4 mm ("reversal of anisocoria"). The left upper lid ptosis disappeared in favor of slight retraction (Fig. 1). In a separate testing session, 0.1% pilocarpine instilled into both eyes did not alter pupil size. Starch-iodine Test We induced sweating by asking the patient to climb a one-step stool several times. The sweating on the right side of the face induced violaceous flushing that was absent on the left side of the face. After application of yellow Departments of Neurophysiology (NA, JME), Neurology (JR), and Dermatology (AT), Hospital del Mar, Barcelona, Spain. Address correspondence to Alberto Galvez, MD, Hospital del Mar, Barcelona, Servicio de Neurologı´a, Paseo Marı´timo 25-29, 08003 Barcelona, Spain; E-mail: algarui@yahoo.com 178 J Neuro-Ophthalmol, Vol. 28, No. 3, 2008 starch-iodine powder to both sides of the forehead, the right forehead skin color became dark blue whereas the left forehead skin remained yellow. This result indicated intact sudomotor function on the right forehead and absent sudomotor function on the left forehead (the rest of the face did not sweat sufficiently to show positivity on either side) (Fig. 1). The Sympathetic Skin Response (SSR) Test The SSR represents an electrical potential generated in skin sweat glands. In healthy subjects younger than 60 years of age, the response is always present throughout the skin of the extremities. It originates through a change in electrical skin resistance caused by skin humidity variation after a pulse of sweat. The SSR is most frequently used in diagnosing functional impairment of nonmyelinated post-ganglionic sudomotor sympathetic fibers in peripheral neuropathies. These fibers are the efferent component of the arc reflex and are activated by somesthetic afferent fibers that enter the spinal cord through the dorsal root and connect with Clark's column. The sympathetic fibers reach the paravertebral ganglionic column by traveling through the anterior roots and nerves. We applied a nociceptive sympathetic stimulus to the right median nerve at the wrist. A few minutes later, the same stimulus was applied to the left median nerve at the wrist. In a healthy person, the SSR should always be present throughout the skin of the extremities. However, in patients with peripheral neuropathies with impairment of nonmyelinated postganglionic sudomotor sympathetic fibers, the SSR will be abnormal, showing a malfunction of the entire autonomic nervous system or part of it. Responses were reduced after stimulation of both the left and the right median nerves (Fig. 2). The response was abolished in the left foot and decreased in amplitude in the left hand. This phenomenon is explained by a reduction in the number of functioning sweat glands or sensory afferent fibers in the left extremities. The absence of a peripheral neuropathy on neurophysiologic tests rules out dysfunction of sensory afferent fibers. The most likely explanation is a reduction of excitability of the sympathetic arc reflex due to impairment of autonomic pathways. Nerve Conduction Velocity Tests of the Median (Including F-wave), Ulnar, Tibial (Including H-reflex), and Sural Nerves Results of these studies were within normal limits. Cardiac Autonomic Reflex Tests Measured by the heart rate variation (R-R interval) after stimulation by deep breathing, Valsalva maneuver, and postural changes (tilting), results of all studies were normal. DISCUSSION In our patient, topical pharmacologic testing con-firmed a left Horner syndrome. Other autonomic testing FIG. 1. Starch-iodine test of sweat function and apraclonidine test. After application of yellow starch-iodine powder to the both sides of the forehead, the right forehead turns purple whereas the left fore-head remains unchanged in color, indicating hypohidrosis of the left forehead. Two drops of 0.5% apra-clonidine have been instilled in both eyes. The previously miotic left pupil is now relatively mydriatic and the previously ptotic left upper lid is now relatively retracted, indicating adrenergic supersensitivity of the left Mu¨ller muscle and iris sphincter, manifestations of a left Horner syn-drome. 179 Horner Syndrome and Anhidrosis J Neuro-Ophthalmol, Vol. 28, No. 3, 2008 confirmed an ipsilateral facial and extremity anhidrosis. Parasympathetic function was normal. He represents an exceptional case because of the extensive unilateral involvement of the sympathetic auto-nomic system (left face and left upper and lower extrem-ities) combined with Horner syndrome. We have found only one similar case (5), a patient with ‘‘crossed'' sym-pathetic dysfunction (left face and right arm). That patient did not have a Horner syndrome. Caparros-Lefebvre et al. (6) reported a patient with Ross syndrome who had unilateral loss of facial sweating and contralateral extremity anhidrosis. That patient and ours probably lie on a spectrum of systemic-multifocal autonomic dysfunction observed in Holmes-Adie, Ross, and Guillain-Barre´ syndromes. Shin et al (7) reported 5 patients with Ross syndrome with pharmacologically confirmed Horner syndrome in 4. These 5 patients showed some degree of systemic autonomic dysfunction. In fact, the SSR was absent in both hands in 2 patients, absent in one hand in 2 patients (the Horner syndrome was ipsilateral to the hand deficit), and absent over the left anterior chest in 1 patient. The authors concluded that the autonomic dysfunction in Ross syndrome could be more extensive than the original description of Ross syndrome in 1958 (8). The harlequin and Horner syndromes may be caused by structural lesions of the sympathetic autonomic path-ways in the hypothalamus, brainstem, spinal cord, and preganglionic or postganglionic sympathetic nerves. There are many causes: iatrogenic (9-13), brain stem stroke (1), massive goiter with secondary sympathetic pathway compression (14), and mediastinal neurinoma (15). However, in many other patients there is no identifiable cause (2,3,5,7,11,16-19), as in our patient. To account for cases in individuals without anatom-ically verifiable lesions, various explanations have been proposed. Lance et al (1) postulated a lesion of the anterior radicular artery in the spinal cord. Drummond et al (18) posited an autoimmune process without clear focality. Shin et al (6) proposed an embryogenic disorder of the neural crest affecting the migration of the derivative cells. Our patient's findings could be explained by a seg-mental dysautonomia caused by an autoimmune process. However, in that case we would expect involvement scat-tered on both sides of the body. For this reason, we postu-late a developmental disorder of neural crest migration. In days 12-15 of embryogenesis, the neural crest, derived from the notochord, adopts a tubular disposition. At that time, the sympathetic cells become localized adjacent to the sulcus limitans on both sides of the basal plaque. A disorder of migration of neural crest cell derivatives at that time could explain an extensive alteration of the sympathetic system. This alteration of the sympathetic system would be unilateral if the migration disorder were localized to only one side of the basal plaque. Several investigators (20,21) have studied the com-plex process of embryologic development of the sympa-thetic neurons derived from the neural crest with human embryonic stem cells (hESCs). This system can be used in the future for studying familial dysautonomia and other partial dysautonomias, helping to clarify the etiology of these overlapping syndromes. In our patient, we cannot rule out an acquired dysautonomia of autoimmune origin, especially consider-ing the patchy involvement of the left face and extremities. REFERENCES 1. Lance JW, Drummond PD, Gandevia SC, et al. Harlequin syndrome: the sudden onset of unilateral flushing and sweating. J Neurol Neurosurg Psychiatry 1988;51:635-42. 2. Kalapesi FB, Krishnan AV, Kiernan MC. Segmental facial anhidrosis and tonic pupils with preserved deep tendon reflexes: a novel autonomic neuropathy. J Neuroophthalmol 2005;25:5-8. FIG. 2. Sympathetic skin response (SSR) test. A. After a nociceptive stimulus was applied to the right hand, there was no SSR in the left foot. Responses recorded in the left extremities (hand and foot) were reduced after stimulation of the left and right median nerves. B. After a nociceptive stimulus was applied to the left hand, there was no SSR in the left foot and a relatively reduced response in the left hand. 180 q 2008 Lippincott Williams & Wilkins J Neuro-Ophthalmol, Vol. 28, No. 3, 2008 Galvez et al 3. Abe M, Tamura A, Sogabe Y, et al. Harlequin sign (hemifacial flushing and contralateral hypohidrosis) in a 4-year-old girl with Horner syndrome. Pediatr Dermatol 2006;23:358-60. 4. American Academy of Ophthalmology. Basic and Clinical Science Course, Neuro-ophthalmology. San Francisco: American Academy of Ophthalmology; 2006. 5. Moon SY, Shin DI, Park SH, et al. Harlequin syndrome with crossed sympathetic deficit of the face and arm. J Korean Med Sci 2005;20: 329-30. 6. Caparros-Lefebvre D, Hache JC, Hurtevent JF, et al. Unilateral loss of facial flushing and sweating with contralateral anhidrosis: Harlequin syndrome or Adie's syndrome? Clin Auton Res 1993;3:239-41. 7. Shin RK, Galetta SL, Ting TY, et al. 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Stem Cells 2005;23: 923-30. 181 Horner Syndrome and Anhidrosis J Neuro-Ophthalmol, Vol. 28, No. 3, 2008 |
