Harlequin Syndrome/Harlequin Sign

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Article initiated by:

Akash Gupta, Andrew Go Lee, MD, Chaow Charoenkijkajorn, M.D.

All contributors:

Mohammad Pakravan, Nagham Al-Zubidi, MD, Anushka Sai Mandalapu, Nagham Al-Zubidi, MD, Chaow Charoenkijkajorn, M.D., Sonali Singh MD

Assigned editor:

Sonali Singh MD

Review:

Assigned status Update Pending

 by Sonali Singh MD on August 8, 2023.

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Contributing Editors:	add

In summary, clinicians should be aware that the Harlequin sign (ipsilateral facial anhidrosis or blanching with contralateral flushing and hyperhidrosis) may be accompanied by a Horner syndrome (ipsilateral ptosis, miosis, anhidrosis). Imaging of the sympathetic axis is recommended in the Harlequin sign to exclude treatable etiologies for the Harlequin syndrome.

Disease Entity

Disease

Harlequin Syndrome, first described by Lance et al in 1988, is the syndrome caused by autonomic nervous system dysfunction. Autonomic Harlequin syndrome should be distinguished from Harlequin ichthyosis (a genetic skin disorder). Autonomic nervous system dysfunction results in the clinical findings of anhidrosis, Horner syndrome, and facial blanching as well as contralateral sweating, and skin flushing. Harlequin syndrome is one of the diseases that can cause Harlequin sign. Harlequin sign refers to the clinical presentation of ipsilateral loss of sympathetic innervation to the chest, neck, and face. This results in sharply demarcated unilateral anhidrosis and facial body blanching with contralateral increased or normal flushing and hyperhidrosis. Harlequin sign can occur in conjunction with Horner syndrome due to an ipsilateral lesion of the oculosympathetic vasodilator neurons combined with hemifacial or hemibody sympathetic anhidrosis. The Harlequin sign is used to describe the physical findings itself, as it may be secondary to a structural lesion such as a tumor, trauma, or iatrogenic injury. Harlequin syndrome refers to a broader context in which the sign appears, including idiopathic or congenital causes.

Pathogenesis

The pathogenesis of Harlequin syndrome is unclear, but it likely involves autonomic dysfunction and disruption of sympathetic innervation to one side of the face, typically at the preganglionic or postganglionic levels. In more than half of reported cases of Harlequin syndrome, the cause is idiopathic. It is common in neonates, associated with hypothalamic functional immaturity and vasomotor instability. Proposed causes for Harlequin syndrome in adults include occlusion of the third thoracic radicular artery, atypical neural crest migration, and autoimmune processes affecting the nerves (Guillan Barre syndrome, diabetic neuropathy) It can occur in conjunction with a Horner’s syndrome (ptosis, miosis, anhidrosis) as well. The symptoms can be brought on by heat stress, exercise, or sudden emotion in the patient.

Diagnosis

History

Patients usually describe an intermittent unilateral facial flushing, tearing of the eyes, and sweating on physical or emotional exertion. In addition, a history of ptosis or miosis may be seen as a concomitant Horner syndrome can be found.

Physical Exam

The main ophthalmic manifestation is the Horner syndrome. Sweat testing or skin perfusion testing with laser Doppler flowmetry can be conducted during exertion or with a body-warming suit to confirm anhidrosis and hyperhidrosis. An ophthalmologic exam can also be done to assess pupil size, pupil response to light and dark, dilation lag, and eyelid ptosis or upside down ptosis.

Signs and Symptoms

On the flowmetry skin perfusion exam minor changes during exertion will be seen unilaterally whereas on the contralateral side a significant increase will be seen. In addition, temperature on either side of the forehead can be taken and a unilateral increase with exertion will be found. In addition, an iodine-starch test can also be used during exertion or body warming to demonstrate the differences in sweat response on each side of the head.

Diagnostic procedures

A Horner syndrome with or without features of the Harlequin sign can be indicative of a lesion in the sympathetic pathway (e.g., trauma, arterial dissection, stroke or malignancy), neuroimaging of the entire sympathetic axis is generally recommended. Targeted sympathetic nervous system imaging should be considered for any unexplained Horner syndrome (e.g., MRI of cervical spine, neck, head, and orbits to thoracic T2 in the chest).

Differential Diagnosis

Other conditions on the differential can include:

• Ross syndrome, in which there is a unilateral or bilateral tonic pupil, hyporeflexia, and segmental anhidrosis.
• Horner syndrome which consists of unilateral miosis, ptosis, and anhidrosis and can sometimes accompany the Harlequin syndrome (up to 46% of patients in one series).
• Holmes-Adie syndrome which consists of tonically dilated pupils with light-near dissociation and tendon areflexia.

General Treatment and Prognosis

The treatment of Harlequin syndrome should be directed at the underlying etiology. Idiopathic Harlequin syndrome (with or without concomitant Horner syndrome) is typically benign and may not require any therapy besides counseling and monitoring. Symptomatic patients should be advised to avoid overheating and overstimulation of the sympathetic axis. Patients who fail conservative therapy might require sympathectomy in extreme cases.