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Show EDITORIAL Harlequin Syndrome: Still Only Half Understood William P. Cheshire, Jr MD, and Phillip A. Low, MD Sympathetic vasodilatory and sudomotor fibers from the stellate ganglion mediate the principal reflex control of human facial thermoregulatory flushing and sweating (1,2). Heat stress, exercise, or sudden emotion in the patient with hemifacial cutaneous sympathetic denervation may elicit a dramatic alteration in facial appearance known as harlequin syndrome, in which a distinct line divides the denervated pale and dry half from the intact red and moist half. At rest, the only visible sign of sympathetic asymmetry may be oculosympathetic paresis, but this is not always present and, in fact, was not apparent in the first description of harlequin syndrome by Lance et al. in 1988 (3). Still other reports of this unusual syndrome have described tonic pupils, indicating a parasympathetic deficit. The literature lacks consensus regarding what, if any, pupillary abnormalities belong with the diagnosis of harlequin syndrome. An article in this issue of the Journal of Neuro-Ophthalmology clarifies the relationship of pupillary abnormalities to harlequin syndrome. Bremner and Smith (4) report pupillographic findings in the largest published series of harlequin syndrome. Of their 39 patients from London's National Hospital at Queen Square, 64% had abnormal pupils, most commonly Horner syndrome (46%) on the nonflushing side. They also found that the oculosympathetic deficit was almost always postganglionic. Whereas harlequin syndrome is usually benign and imaging studies are unrevealing, it is worth noting that in this series 1 patient in whom topical hydroxyamphetamine indicated a preganglionic oculosympathetic deficit had been treated for an apical lung (Pancoast) tumor. Another 13% had tonic pupils with attenuated light responses, slow but exaggerated near responses with light-near dissociation, and sector palsy, and 2 patients had supersensitivity to 0.1% pilocarpine. The tonic pupils had gone unnoticed by all but 1 patient. Sympathetic or parasympathetic pupillary abnormalities were bilateral in 15%, and combined sympathetic and parasympathetic deficits occurred in 7%. Of note, 23% had asymmetric or absent deep tendon reflexes, and 13% had signs of generalized autonomic failure. Also in this issue, Galvez et al. (5) describe exercise-induced right hemifacial flushing and sweating in a patient with a left Horner syndrome. The interesting feature is that the starch-iodine test disclosed left hemifacial anhidrosis, and the sympathetic skin response, although intact on the right, was decreased in the left hand and abolished in the left foot. Lance et al. (3) named this bipartite facial discoloration harlequin syndrome after the mischievous character in the Italian improvisational theater, the Commedia dell'Arte. Unlike some modern versions of Harlequin, which split his face into two colors, the original 16th century character's mask was symmetrical and his costume was illustriously variegated in triangular patchwork (6). Accumulating evidence indicates that, like the original Harlequin's irregular costume, the dysautonomia underlying harlequin syndrome is not always confined to the skin of the face but may be more widespread than previously recognized. Some cases of harlequin syndrome may be diffuse or patchy in their distribution, combining sympathetic and parasympathetic lesions (4) or facial and limb anhidrosis (5). Department of Neurology (WPC) Mayo Clinic, Jacksonville, Florida; and Department of Neurology (PAL), Mayo Clinic, Rochester, Minnesota. Address correspondence to; E-mail: cheshire@mayo.edu J Neuro-Ophthalmol, Vol. 28, No. 3, 2008 169 These detailed investigations, combined with pre-vious anecdotal observations, indicate that harlequin syndrome overlaps with several other syndromes. Among them is Holmes-Adie syndrome, which is characterized by tonic pupils with asymmetric or absent tendon reflexes, as were found in five of the patients of Bremner and Smith (4). Harlequin syndrome has also been described in association with Ross syndrome, which is a partial dysautonomia comprising the clinical triad of unilateral or bilateral tonic pupils, segmental anhidrosis involving the face or body, and tendon hyporeflexia (7,8). The detection of subclinical tonic pupils in a subset of patients with harlequin syndrome (4), as well as previous studies demonstrating subclinical anhidrosis in patients with Holmes-Adie syndrome (9,10), supports the conclu-sion that these syndromes may lie along the same nosologic spectrum. Alternatively, harlequin syndrome may simply be a highly visible final common dysautonomic manifestation of many disorders that asymmetrically target facial sympathetic vasomotor innervation, including occasionally Guillain-Barre´ syndrome, pure autonomic failure, multiple system atrophy, diabetic autonomic neuropathy, and neo-plastic and traumatic lesions of the stellate ganglion. The hypothesis advanced by Galvez et al. (5), that segmental dysautonomia might have reflected asymmetri-cal migration of neural crest cells during embryogenesis, would not account for the sudden appearance of symptoms during adulthood or the absence of heterochromia iridis. Harlequin syndrome is typically acquired, and the etiology of injury or degeneration of cholinergic ganglion cells or their postganglionic projections remains elusive. Perhaps harlequin syndrome results from regional depletion of a neurotrophic factor. Neurturin, for example, has been shown to be important for the maintenance of both parasympathetic (11) and sympathetic (12) cholinergic postganglionic neurons. Harlequin syndrome might also result from regional infection by a neurotrophic virus. The pathogenic virus might have a preference for the stellate ganglion, as does herpes simplex virus for the geniculate ganglion in Bell's palsy. Of interest, Ross syndrome has recently been described in a patient with acute cytomegalovirus infection (13), and tonic pupils have been reported as a complication of infection by varicella (14), parvovirus (15), and human herpesvirus 6 (16). The elucidation of harlequin syndrome, it seems, has reached the halfway mark. REFERENCES 1. Drummond PD. Sweating and vascular responses in the face: normal regulation and dysfunction in migraine, cluster headache and harlequin syndrome. Clin Auton Res 1994;4:273-85. 2. Drummond PD, Finch PM. Reflex control of facial flushing during body heating in man. Brain 1989;112:1351-8. 3. 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. 4. Bremner F, Smith S. Pupillographic findings in 39 consecutive cases of harlequin syndrome. J Neuroophthalmol 2008;28:171-7. 5. Galvez A, Ailouti N, Toll A, et al. Horner syndrome associated with ipsilateral facial and extremity anhidrosis. J Neuroophthalmol 2008;28:178-81. 6. Sand M. The History of the Harlequinade. London: Benjamin Blom; 1915. 7. Shin RK, Galetta SL, Ting TY, et al. Ross syndrome plus: beyond Horner, Holmes-Adie, and harlequin. Neurology 2000;55:1841-6. 8. Drummond PD, Edis RH. Loss of facial sweating and flushing in Holmes-Adie syndrome. Neurology 1990;40:847-9. 9. Nolano M, Provitera V, Perretti A, et al. Ross syndrome: a rare or a misknown disorder of thermoregulation? A skin innervation study on 12 subjects. Brain 2006;129:2119-31. 10. Wolfe GI, Galetta SL, Teener JW, et al. Site of autonomic dysfunction in a patient with Ross syndrome and postganglionic Horner's syndrome. Neurology 1995;45:2094-6. 11. Wanigasekara Y, Keast JR. Neurturin has multiple neurotrophic effects on adult rat sacral parasympathetic ganglion neurons. Eur J Neurosci 2005;22:595-604. 12. Hiltunen PH, Airaksinen MS. Sympathetic cholinergic target innervation requires GDNF family receptor GFRa2. Mol Cell Neurosci 2004;26:450-7. 13. Nagane Y, Utsugisawa K. Ross syndrome associated with cytomeg-alovirus infection. Muscle Nerve 2008;36:924-26. 14. Heger T, Kolling GH, Dithmar S. Atypical tonic pupil as a compli-cation of chickenpox infection. Ophthalmologe 2003;100:330-3. 15. Corridan PG, Laws DE, Morrell AJ, et al. Tonic pupils and human parvovirus (B19) infection. J Clin Neuroophthalmol 1991;11: 109-10. 16. Oberacher-Velten IM, Jonas JB, Ju¨nemann A, et al. Bilateral optic neuropathy and unilateral tonic pupil associated with acute human herpesvirus 6 infection: a case report. Graefes Arch Clin Exp Ophthalmol 2005;243:175-7. 170 q 2008 Lippincott Williams & Wilkins J Neuro-Ophthalmol, Vol. 28, No. 3, 2008 Editorial |
