Unilateral loss of hemifacial sudomotor and vasomotor activity with normal ocular sympathetic innervation was first described by Lance and Drummond (1) in five patients with unilateral facial anhidrosis and reduced facial flushing in the absence of the characteristic pupillary abnormalities of Horner syndrome. The authors named this condition "Harlequin syndrome" after the Italian clown or English pantomime character (1,2). Autonomic testing in these patients, involving electrical stimulation of the motor cortex, suggested a selective lesion affecting the second thoracic nerve root, thus explaining the unilateral facial abnormalities with relative sparing of the sympathetic innervation to the pupil. In certain patients, unilateral facial anhidrosis may coexist with tonic pupils and depressed deep tendon reflexes, now referred to as Ross syndrome (3,4).
The present case report describes an unusual case of unilateral facial anhidrosis in conjunction with bilateral tonic pupils and preserved deep tendon reflexes, adding to the spectrum of focal autonomic disorders characterized by pupillary dysautonomia and facial sudomotor and vasomotor changes.
A 31-year-old woman had a 2-year history of right-sided hemifacial flushing and sweating after moderate physical exertion. Her partner first noticed this after they had been rollerblading. Subsequently, she noticed the development of right-sided facial flushing and sweating of the right forehead, nose, cheek, and chin starting approximately 30 minutes after vigorous gardening, playing netball, going to the gym, and swimming. Other precipitants included eating chilies and spicy meals.
Over the same 2-year period, the patient had observed the development of relative dilatation of the left pupil, the size of which varied during the course of the day. There was no history of ptosis, diplopia, or ocular pain.
There was no history of syphilis, varicella zoster, ocular trauma, previous spinal surgery, migraine, or other headache. The patient did not have diabetes mellitus or describe palpitations or postural dizziness that may have suggested the presence of a generalized autonomic disturbance.
Uncorrected visual acuities were 20/15 OD and 20/20 OS. There was no ptosis. The right pupil measured 5 mm and the left pupil 7 mm in dim illumination. Pupillary reaction to direct light was absent bilaterally. There was a slow tonic near response accompanied by slow redilatation on fixating a distant target. The patient did not have a relative afferent pupillary defect.
Slit-lamp examination revealed vermiform movements of the pupil margin with sectoral paralysis of the iris sphincter OU. Intraocular pressures were 18 mm Hg OU. Color vision was normal on Ishihara plate examination. Ophthalmoscopy was normal. Visual fields were full to confrontation. Cranial nerve examination was otherwise normal.
There was no apparent difference in facial color or sweating between the two sides of the face at room temperature. On exertion, however, there was loss of flushing and sweating over the left side of the face, whereas the right side appeared normally flushed and moist with perspiration (Fig. 1). Limb examination revealed symmetrically normal muscle bulk, tone, and power. Importantly, deep tendon reflexes were easily elicited in all four limbs. There were no sensory abnormalities. There was no postural hypotension or other clinical features to suggest the presence of a generalized autonomic disturbance.
Magnetic resonance imaging (MRI) of the cervical and upper thoracic cord was normal. The patient then became pregnant and declined topical pharmacological evaluation of ocular autonomic dysfunction because of concerns of teratogenicity (5).
A diagnosis of Harlequin syndrome with bilateral Adie syndrome was made to explain the unusual combination of signs. The preservation of deep tendon reflexes excluded a diagnosis of Ross syndrome.
Harlequin syndrome has been described as an isolated finding (6,7), in association with a superior mediastinal neurinoma along the preganglionic sympathetic pathway (8), or postoperatively (9-11). Internal jugular catheterization (9), neck surgery (10), and bilateral sympathectomy for hyperhidrosis have also been described as precipitants of the syndrome.
The right-sided facial flushing of our patient is on the side of an intact sympathetic pathway. As pointed out by Lance and Drummond (1), the flushing and sweating experienced on the sympathetically intact side may be an overreaction to the contralateral denervation to provide normal heat control. Sympathetic hyperactivity has been reported contralateral to a cervical sympathectomy (11).
The apparent dissociation between intact sympathetic function in the eye and unilaterally impaired vasomotor sympathetic function on the face in our patient could be explained by the fact that most sympathetic fibers destined for the pupil and levator palpebrae superioris (LPS) leave the spinal cord in the first thoracic root above T2. The cervical sympathetic pathway is a three-neuron pathway. The first neuron (preganglionic) passes from the hypothalamus through the brainstem to the intermediolateral column in the thoracic spinal cord; the second (also preganglionic) neuron passes from the spinal cord through the stellate ganglion to the superior cervical ganglion, where it synapses; and the third (postganglionic) neuron passes from the superior cervical ganglion to the pupil, the LPS muscle, blood vessels of the eye and face, and the sweat glands of the face (Fig. 2).
Although vasodilator and sudomotor fibers destined for blood vessels and sweat glands of the face arise between the eighth cervical and fourth thoracic levels, most fibers appear to arise from the second and third thoracic levels (1,12,13). Hence, a preganglionic, second-order neuronal sympathetic lesion in the T2 or T3 root might explain the loss of facial sweating and flushing without the occurrence of Horner syndrome (Fig. 2). In their original report, Lance and Drummond (1) postulated that ischemia from anterior radicular artery occlusion from thoracic torsion during strenuous exercise might underlie Harlequin syndrome. In our patient, no lesion was detected on MRI of the spinal cord. Nor would a lesion at the T2-T3 spinal segments explain the Adie syndrome in our patient.
Another localizing feature is the territory of sweating impairment, specifically whether it is hemifacial or merely limited to the upper face. Previous studies have shown that lesions distal to the bifurcation of the common carotid artery cause impairment of sweating confined to the forehead, periocular skin, and upper nose, whereas more proximal lesions produce sudomotor and vasomotor loss involving half of the face unless the lesion lies in the brachial plexus. Fibers innervating sweat glands and blood vessels of the medial forehead travel intracranially with the internal carotid artery, whereas fibers supplying the entire hemiface travel with the external carotid artery (6,12,14,15). Our patient experienced hemifacial loss of facial sweating and flushing. This could place the lesion proximal to the bifurcation of the common carotid artery.
However, the occurrence of tonic pupils together with hemifacial anhidrosis in our patient suggests that both parasympathetic and sympathetic fibers are involved(15), with the sympathetic deficit being either preganglionic or postganglionic and the parasympathetic lesion being postganglionic (16).
Patients with unilateral facial anhidrosis characteristic of Harlequin syndrome have been noted to exhibit Adie syndrome, including tonic pupils and reduced deep tendon reflexes (15,18,19), a combination called Ross syndrome after the original description in 1958 (3).
In our patient, deep tendon reflexes were preserved, thus differentiating the condition from Ross's original description (3). As previously suggested (15), the categorization of patients into syndromes such as Adie (tonic pupils ± hyporeflexia), Ross (segmental anhidrosis, tonic pupils, and hyporeflexia) and Harlequin (segmental or hemifacial anhidrosis without Horner syndrome) have become less stringent because considerable overlap has been noted. It is likely that there exists a spectrum of disorders of partial autonomic neuropathies with variable involvement of the dorsal root ganglia affecting deep tendon reflexes (2,15,17).
A generalized disorder of acetylcholine-releasing nerve terminals would explain the tonic pupils and the hemifacial sudomotor and vasomotor loss observed in the present case (19). Other postulated causes include a disorder of neural crest cell derivatives (15) or microvascular ischemia mediated by an autoimmune process or infectious agent (6).
The localized autonomic disturbances described in the present case are typically benign and warrant no treatment. However, contralateral stellate ganglionectomy remains an option should the patient find unilateral color and sweating changes a social embarrassment.
The authors thank Medical illustrations at Prince of Wales Hospital and Professor Jim Lance for his comments and informed discussion, particularly regarding the cause of Harlequin syndrome.
1. Lance JW, Drummond PD, Gandevia SC, et al. Harlequin syndrome: the sudden onset of unilateral flushing and sweating. J Neurol Neurosurg Psychiatry.
2. Drummond PD, Lance JW. Site of autonomic deficit in harlequin syndrome: local autonomic failure affecting the arm and the face. Ann Neurol.
3. Ross AT. Progressive selective sudomotor denervation; a case with coexisting Adie's syndrome. Neurology.
4. Weller M, Wilhelm H, Sommer N, et al. Tonic pupil, areflexia, and segmental anhidrosis: two additional cases of Ross syndrome and review of the literature. J Neurol.
5. Australian Medicines Handbook,
2nd ed. Adelaide: Wakefield Press; 2000.
6. Drummond PD. The effect of sympathetic blockade on facial sweating and cutaneous vascular responses to painful stimulation of the eye. Brain.
7. Corbett M, Abernethy DA. Harlequin syndrome. J Neurol Neurosurg Psychiatry.
8. Noda S. Harlequin syndrome due to superior mediastinal neurinoma. J Neurol Neurosurg Psychiatry.
9. Coleman PJ, Goddard JM. Harlequin syndrome following internal jugular vein catheterization in an adult under general anesthetic. Anesthesiology
10. Turco GR, Farber NE. Postoperative autonomic deficit: a case of harlequin syndrome. Anesthesiology.
11. Guttmann L. The distribution of disturbances of sweat secretion after extirpation of certain sympathetic cervical ganglia in man. J Anat.
12. Morris JG, Lee J, Lim CL. Facial Sweating in Horner's syndrome. Brain.
13. Goetz RH. The Surgical Physiology of the sympathetic nervous system with special reference to cardiovascular disorders. Int Abstracts Surg.
14. Drummond PD. The mechanism of facial sweating and cutaneous vascular responses to painful stimulation of the eye. Brain.
15. Shin RK, Galetta SL, Ting TY, et al. Ross syndrome plus: beyond horner, Holmes-Adie, and harlequin. Neurology.
16. Harriman DG, Garland H. The pathology of Adie's syndrome. Brain.
17. Drummond PD, Edis RH. Loss of facial sweating and flushing in Holmes-Adie syndrome. Neurology.
18. Spector RH, Bachman DL. Bilateral Adie's tonic pupil with anhidrosis and hyperthermia. Arch Neurol.
19. Hardin WB Jr, Gay AJ. The phenomenon of benign areflexia. Review of the Holmes-Adie syndrome with case reports and a study of the Achilles reflex. Neurology.