Harlequin syndrome

Harlequin Syndrome: A Comprehensive Medical Review

Introduction

Harlequin syndrome is a rare autonomic neurological disorder characterized by sudden onset of unilateral facial flushing and sweating, with the contralateral side remaining pale and dry. Named after the colorfully costumed Harlequin character from Commedia dell’Arte, the syndrome was first comprehensively described by Lance, Drummond, Gandevia, and Morris in 1988 in the Journal of Neurology, Neurosurgery, and Psychiatry.^[1][2][3][4]

According to the National Institutes of Health StatPearls medical reference and peer-reviewed literature, Harlequin syndrome results from unilateral blockade of the T2-T3 sympathetic nerve fibers that carry sudomotor (sweating) and vasomotor (blood vessel control) supply to the face. The condition affects the autonomic nervous system (ANS), which controls involuntary bodily functions including perspiration, skin flushing, pupil response, and thermoregulation.^[3][5][6]

According to a comprehensive 2024 study from the Mayo Clinic analyzing 51 patients over 26 years, Harlequin syndrome has a median age of onset at 52 years (range 8-73 years) and shows a strong female predominance, with 76% of cases occurring in women. The condition is generally benign and does not require treatment in most cases, though it can cause significant psychological distress due to the dramatic cosmetic asymmetry.^[7][8][9]

Etiology and Pathophysiology

Anatomical Basis

The pathophysiology of Harlequin syndrome involves dysfunction of the sympathetic pathway controlling facial thermoregulation and vasomotor function:^[2][6][1]

Sympathetic Pathway Anatomy:

• Hypothalamus: Origin of descending sympathetic pathways
• Brainstem: Medullary and pontine relay stations
• Spinal cord: Descending pathways through cervical and upper thoracic segments
• T2-T3 sympathetic ganglia: Critical junction where most lesions occur
• Stellate ganglion: Fusion of inferior cervical and first thoracic ganglia
• Postganglionic fibers: Ascend to innervate facial structures^[6][2]

Mechanism of Asymmetry:
According to the seminal work by Lance et al., the characteristic unilateral facial appearance results from a deficit in the sympathetic pathway on the non-flushing side, while the flushing side demonstrates normal or compensatory excessive sympathetic activity:^[2][6]

• Affected side: Anhidrosis (absence of sweating) and absent flushing due to sympathetic denervation
• Unaffected side: Normal or enhanced flushing and sweating, often appearing exaggerated due to contrast
• Demarcation line: Sharp midline or paramedian border between affected and unaffected areas^[9][2]

Classification System

The literature distinguishes between Harlequin syndrome and Harlequin sign based on the presence of ocular sympathetic involvement:^[1][2]

Harlequin Syndrome (True):

• Hemifacial flushing and sweating asymmetry
• Normal ocular sympathetic function (no Horner syndrome)
• Isolated sudomotor and vasomotor dysfunction
• May be idiopathic or secondary^[1][2]

Harlequin Sign:

• Hemifacial flushing and sweating asymmetry
• Associated with Horner syndrome (ptosis, miosis, anisocoria)
• Indicates sympathetic lesion at T1 level affecting oculosympathetic fibers
• More likely to have identifiable structural cause^[4][1]

Etiological Categories

According to the Mayo Clinic series of 51 patients, Harlequin syndrome can be classified by etiology:^[8]

1. Idiopathic (37% of cases):

• No identifiable underlying cause
• Most common presentation
• Presumed microvascular or inflammatory damage to sympathetic chain
• Benign course^[8][6]

2. Postsurgical (17% of cases):
The most common secondary cause includes various surgical procedures:^[10][11][8]

• Thoracotomy: Lung resection, cardiac surgery
• Neck surgery: Carotid endarterectomy, thyroidectomy
• Sympathectomy: Intentional or iatrogenic sympathetic interruption
• Mediastinal procedures: Anterior chest wall operations^[10][8]

3. Neoplasm (9.8% of cases):

• Pancoast tumor: Superior sulcus lung tumors
• Mediastinal masses: Lymphoma, thymoma
• Cervical tumors: Thyroid carcinoma
• Metastatic disease: Compressing sympathetic chain^[8]

4. Trauma (7.8% of cases):

• Cervical spine injury: Whiplash, fractures
• Birth trauma: Forceps delivery, shoulder dystocia
• Penetrating injury: Stab or gunshot wounds
• Blunt trauma: Motor vehicle accidents^[8]

5. Small Fiber Neuropathy (7.8% of cases):

• Diabetes mellitus: Most common cause
• Amyloidosis: AL or hereditary types
• Autoimmune disorders: Sjögren syndrome, lupus
• Infections: HIV, Lyme disease^[12][8]

6. Systemic Causes (5.9% of cases):

• Multiple sclerosis: Demyelinating lesions affecting autonomic pathways
• Stroke: Brainstem or spinal cord infarction
• Syringomyelia: Cervical or thoracic cord cavitation
• Tumors: Spinal cord or brainstem neoplasms^[8]

7. Autoimmune (5.9% of cases):

• Autoimmune autonomic ganglionopathy: Antibodies against ganglionic acetylcholine receptors
• Guillain-Barré syndrome: Acute inflammatory demyelinating polyneuropathy
• Sarcoidosis: Granulomatous infiltration^[12][8]

8. Pure Autonomic Failure (3.9% of cases):

• Chronic degenerative autonomic disorder
• Harlequin syndrome as presenting feature
• Associated with α-synuclein pathology^[13][8]

9. Regional Anesthesia Complication:

• Epidural or spinal anesthesia complications
• Usually transient, resolving as anesthesia wears off
• Can indicate unintended thoracic sympathetic blockade^[11]

10. Veno-Arterial ECMO Complication:

• Differential hypoxemia of upper vs. lower body
• Results from competing blood flow sources
• Requires specific management strategies^[14][3]

Clinical Presentation

Demographics and Epidemiology

According to published case series and recent large studies:^[9][8]

Prevalence and Demographics:

• Rarity: Exact prevalence unknown; considered very rare
• Gender: 76% female predominance in Mayo Clinic series
• Age of onset: Median 52 years (range 8-73 years)
• Onset pattern:
  • Acute/subacute in 57% of postsurgical cases
  • Insidious in 89% of non-surgical cases^[8]

Cardinal Clinical Features

The hallmark presentation involves dramatic hemifacial asymmetry triggered by specific stimuli:^[15][3][2]

Primary Symptoms:

Unilateral Absence of Sweating and Flushing:
On the affected side:^[15][6][2]

• Anhidrosis: Complete absence of sweating on affected half of face, neck, and sometimes upper chest
• Absent flushing: Pale, non-reactive skin that doesn’t redden
• Cool skin: Lower temperature on affected side
• Dry texture: Absence of moisture despite triggers^[16][2]

Contralateral Enhanced Response:
On the unaffected side:^[3][2][15]

• Profuse sweating: Often excessive, compensatory hyperhidrosis
• Marked flushing: Intense reddening and warmth
• Warm, moist skin: Exaggerated thermoregulatory response
• Sharp demarcation: Distinct midline or paramedian border^[15][9]

Triggering Factors

Symptoms are typically provoked by specific stimuli that normally induce sweating and flushing:^[2][3][15]

• Physical exercise: Vigorous exertion or sustained activity
• Heat exposure: Hot weather, warm environments, hot showers
• Emotional stress: Anxiety, embarrassment, excitement
• Spicy foods: Gustatory sweating response
• Alcohol consumption: Vasodilatory effects^[2][15]

Associated Features

Pupillary Abnormalities (25.5% of patients):
When present, suggest Harlequin sign rather than pure syndrome:^[1][8]

• Horner syndrome: Ptosis, miosis, enophthalmos on affected side
• Tonic pupils: Abnormal pupillary responses to light
• Anisocoria: Unequal pupil sizes^[4][8]

Neurological Signs (33.3% of patients):

• Abnormal muscle stretch reflexes: Reduced or absent reflexes
• Sensory changes: Numbness or paresthesias
• Weakness: Upper extremity weakness in some cases^[8]

Associated Comorbidities:

• Headache (39% of patients): Cluster headaches, migraines
• Cluster headache syndrome: Trigeminal autonomic cephalalgia
• Nasal discharge: Rhinorrhea during symptomatic episodes
• Lacrimation: Tearing on affected or unaffected side^[3][8]

Clinical Presentation Patterns

Distribution of Involvement:

• Face: Most common, involving forehead, cheeks, and nose
• Neck: Often extends to ipsilateral neck
• Upper chest: May involve superior thoracic region
• Arms: Occasionally extends to upper extremities^[3][15]

Temporal Pattern:

• Episode duration: Minutes to hours per episode
• Frequency: Variable, from daily to occasional
• Progression: Generally stable over time
• Spontaneous resolution: Rare, except in iatrogenic cases^[11][2]

Diagnosis

Clinical Diagnostic Approach

Diagnosis is primarily clinical, based on characteristic presentation and confirmed through specialized testing:^[7][16][6]

Diagnostic Criteria:
According to expert consensus:^[16][6]

1. Unilateral absence of facial flushing and sweating
2. Normal or excessive flushing and sweating on contralateral side
3. Sharp demarcation at facial midline
4. Triggered by heat, exercise, or emotion
5. Absence of other neurological deficits (in pure Harlequin syndrome)

Clinical Evaluation

Comprehensive History:
Essential elements to identify etiology:^[7][16][8]

• Onset: Acute vs. gradual, triggers, duration
• Past medical history: Diabetes, autoimmune disease, cancer
• Surgical history: Thoracic, neck, or sympathetic procedures
• Trauma history: Cervical spine injury, birth trauma
• Medication history: Sympathomimetic or sympatholytic drugs^[16][7]

Physical Examination:
Neurological Assessment:

• Pupillary examination: Assess for Horner syndrome (ptosis, miosis, anisocoria)
• Cranial nerves: Complete evaluation
• Motor and sensory: Upper extremity examination
• Reflexes: Muscle stretch reflexes and pathological reflexes
• Coordination: Cerebellar testing^[7][16][8]

Provocation Testing:

• Exercise challenge: Observe response during physical activity
• Heat exposure: Warm room or hot towel application
• Emotional stimuli: Stress or anxiety-provoking situations^[16]

Autonomic Function Testing

Thermoregulatory Sweat Test (TST):
The gold standard for documenting sudomotor dysfunction:^[7][8]

• Method: Patient covered with alizarin red indicator powder and exposed to warm environment (45-50°C)
• Normal response: Powder changes color with sweating
• HS finding: Unilateral absence of color change on affected side
• Quantification: Percentage of body surface with anhidrosis
• Mayo Clinic data: Median anhidrosis 9% (range 0.6-63%)^[8]

Autonomic Reflex Screen (ARS):
Comprehensive autonomic testing battery:^[7][8]

• Cardiovascular reflexes: Heart rate variability with deep breathing
• Valsalva maneuver: Blood pressure and heart rate responses
• Tilt table testing: Orthostatic blood pressure changes
• Quantitative sudomotor axon reflex test (QSART): Sweat response measurement
• Composite Autonomic Severity Score (CASS): Median score 1 (IQR 0-3) in Mayo series^[8]

Other Autonomic Tests:

• Skin biopsy: Evaluate intraepidermal nerve fiber density (small fiber neuropathy)
• Microneurography: Record muscle and skin sympathetic nerve activity
• Pharmacological testing: Pilocarpine iontophoresis to assess sweat gland function^[7]

Imaging Studies

Magnetic Resonance Imaging (MRI):
Essential to exclude structural lesions:^[16][7][8]

• Brain MRI: Rule out brainstem lesions, stroke, demyelination
• Cervical spine MRI: Assess for syringomyelia, tumors, compression
• Thoracic spine MRI: Evaluate sympathetic chain region (T1-T4)
• Contrast enhancement: Identify inflammatory or neoplastic processes^[16][7]

Computed Tomography (CT):

• Chest CT: Assess for Pancoast tumor, mediastinal masses, lung pathology
• CT angiography: Evaluate vascular anomalies or aneurysms^[8]

Ultrasound:

• Thyroid ultrasound: Evaluate thyroid masses
• Carotid Doppler: Assess cervical vascular structures^[7]

Electrophysiological Studies

• Nerve conduction studies: Rule out peripheral neuropathy
• Somatosensory evoked potentials: Assess spinal cord integrity
• Motor evoked potentials: From motor cortex to intercostal muscles (may show prolonged latency)^[2]

Differential Diagnosis

Harlequin syndrome must be differentiated from other causes of facial asymmetry:^[5][3][16]

Primary Differential Diagnoses:

1. Horner Syndrome:

• Similarities: Unilateral facial changes
• Key differences: Classic triad (ptosis, miosis, anisocoria), no flushing asymmetry
• Etiology: First-order (central), second-order (preganglionic), or third-order (postganglionic) lesions^[4][3]

2. Frey Syndrome (Auriculotemporal Syndrome):

• Similarities: Hemifacial sweating and flushing
• Key differences: Triggered by chewing or eating (gustatory sweating), history of parotid surgery or trauma
• Location: Temporal and auricular regions^[3]

3. Rosacea:

• Similarities: Facial flushing and redness
• Key differences: Bilateral, chronic inflammatory condition, papules and pustules
• Triggers: Alcohol, spicy foods, temperature changes^[3]

4. Ross Syndrome:

• Similarities: Segmental anhidrosis
• Key differences: Tonic pupils (Adie’s pupils), hyporeflexia, may involve multiple body regions
• Pathophysiology: Progressive autonomic dysfunction^[3]

5. Cluster Headache:

• Similarities: Hemifacial autonomic features
• Key differences: Severe unilateral orbital/temporal pain, lacrimation, rhinorrhea
• Duration: Brief episodes (15-180 minutes)
• Treatment: Responsive to triptans and oxygen^[15][3]

Management and Treatment

Treatment Philosophy

According to consensus from multiple sources, Harlequin syndrome is generally a benign condition that does not require treatment in most cases:^[11][9][7]

Treatment Indications:

• Psychological distress: Social embarrassment from cosmetic asymmetry
• Severe symptoms: Profuse, disabling hyperhidrosis on unaffected side
• Underlying condition: Treatment of identifiable secondary causes
• Patient preference: Desire for symptom improvement^[17][9][7]

Conservative Management

Reassurance and Education:
The cornerstone of management:^[17][9][7]

• Benign nature: Emphasize lack of serious health consequences
• Favorable prognosis: Condition typically stable, non-progressive
• Cosmetic strategies: Makeup, clothing choices to minimize appearance
• Trigger avoidance: Limit exposure to known precipitants when possible^[9][17]

Psychological Support:

• Counseling: Address social anxiety and embarrassment
• Support groups: Connect with others experiencing similar conditions
• Cognitive behavioral therapy: Manage psychological impact^[9][7]

Pharmacological Management

Botulinum Toxin Injections:
Effective for managing compensatory hyperhidrosis on unaffected side:^[18][17][7]

• Mechanism: Blocks acetylcholine release at neuromuscular junctions and sweat glands
• Technique: Intradermal injections into hyperhidrotic areas
• Efficacy: 80-90% reduction in sweating
• Duration: 4-6 months, requiring repeated treatments
• Safety: Well-tolerated with minimal side effects^[18][17]

Side Effects:

• Local pain at injection sites
• Temporary muscle weakness (if injected too deeply)
• Compensatory sweating in other areas^[18]

Interventional Procedures

Stellate Ganglion Block:
Temporary sympathetic blockade for diagnostic and therapeutic purposes:^[10][17][7]

• Technique: Local anesthetic injection near stellate ganglion (C7-T1)
• Duration: Hours to days per injection
• Uses:
  • Diagnostic test before permanent sympathectomy
  • Repeated blocks for symptom control
  • Assessment of patient tolerance^[17][10]

Advantages:

• Reversible, low-risk procedure
• Can be repeated as needed
• Helps predict sympathectomy outcomes^[17][7]

Surgical Management

Contralateral Sympathectomy:
Surgical interruption of sympathetic chain on the unaffected side:^[10][11][7]

Rationale:

• Eliminates compensatory excessive flushing and sweating
• Creates bilateral symmetry through bilateral sympathetic deficit
• Permanent solution for severe cases^[11][10]

Surgical Approaches:

• Endoscopic thoracic sympathectomy (ETS): Minimally invasive, most common approach
• Open costotransversectomy: Direct surgical access to sympathetic chain
• T2-T3 sympathectomy: Target specific ganglia controlling facial vasomotor/sudomotor function^[10][2]

Outcomes:
According to published case reports:^[10]

• Symptom resolution: Elimination of asymmetric flushing in successful cases
• Patient satisfaction: Generally high in properly selected patients
• Complications: Compensatory sweating in other body regions (30-80% of patients)^[19][10]

Risks and Complications:

• Compensatory hyperhidrosis: Excessive sweating in trunk, groin, legs
• Gustatory sweating: Sweating while eating
• Permanent bilateral anhidrosis: Loss of thermoregulatory capacity
• Horner syndrome: If sympathetic fibers damaged
• Phantom sweating: Sensation of sweating without actual moisture
• Pneumothorax: Surgical complication^[19][17][10]

Selection Criteria:
Surgery should be reserved for:^[19][7]

• Severe psychological distress unresponsive to conservative measures
• Failed pharmacological and interventional treatments
• Motivated, well-informed patients
• Absence of contraindications
• Realistic expectations about outcomes and risks^[19][7]

Treatment of Underlying Causes

When secondary Harlequin syndrome is identified:^[7][8]

• Tumor resection: For compressive masses
• Immunosuppression: For autoimmune ganglionopathy
• Glycemic control: For diabetic autonomic neuropathy
• Specific treatments: Targeted therapy for identified etiology^[12][8]

Management of Iatrogenic Cases

Post-Anesthesia Harlequin Syndrome:
Usually self-limited:^[11]

• Observation: Monitor as anesthesia wears off
• Head elevation: Upright positioning
• Reduce/stop infusion: Taper epidural or spinal anesthesia
• Resolution: Typically hours to days^[11]

Post-Surgical Harlequin Syndrome:
May be transient or permanent:^[10][8]

• Wait and observe: Many cases improve over weeks to months
• Physical therapy: Maintain range of motion
• Stellate ganglion blocks: If persistent and bothersome
• Sympathectomy: Consider if permanent and disabling^[10]

Prognosis and Long-term Outcomes

Natural History

According to long-term follow-up studies and clinical experience:^[9][7][8]

Idiopathic Cases:

• Benign course: No progression to serious disease
• Stable symptoms: Typically remain unchanged over years
• Quality of life: Generally good, primarily cosmetic concerns
• Life expectancy: Normal^[9]

Secondary Cases:

• Depends on etiology: Prognosis determined by underlying cause
• Tumor-related: May improve with tumor treatment
• Post-surgical: May resolve partially over months
• Autoimmune: May respond to immunotherapy^[8]

Quality of Life Considerations

Psychological Impact:
Significant for many patients:^[9][7]

• Social embarrassment: Visible asymmetry causes self-consciousness
• Anxiety: Anticipatory worry about triggering episodes
• Depression: Secondary to chronic cosmetic concerns
• Social withdrawal: Avoidance of situations that trigger symptoms^[9]

Functional Impact:

• Heat intolerance: Impaired thermoregulation on affected side
• Exercise limitation: Some patients avoid activities that trigger symptoms
• Occupational concerns: May affect work in hot environments
• Minimal physical disability: No impairment of motor or sensory function^[15][7]

Prognostic Factors

Favorable Prognosis:

• Idiopathic origin
• No associated neurological deficits
• Successful coping strategies
• Minimal psychological impact^[9][8]

Less Favorable Prognosis:

• Underlying malignancy
• Progressive autonomic failure
• Severe psychological distress
• Multiple comorbidities^[13][8]

Research Directions and Future Perspectives

Pathophysiological Research

Mechanisms of Asymmetry:
Ongoing investigation into why sympathetic dysfunction affects only one side:^[1][2]

• Vascular supply: Unilateral ischemia to sympathetic ganglia
• Autoimmune targeting: Lateralized immune attack
• Anatomical variations: Individual differences in sympathetic innervation
• Central dysregulation: Hypothalamic or brainstem mechanisms^[1]

Incomplete Development Hypothesis:
Some researchers propose incomplete hypothalamic development as a mechanism, particularly in neonatal cases.^[7]

Diagnostic Advances

Improved Autonomic Testing:

• High-resolution imaging: Better visualization of sympathetic chain
• Functional imaging: PET or SPECT to assess sympathetic activity
• Biomarker development: Serum markers of autonomic dysfunction
• Genetic testing: Identification of susceptibility genes^[7]

Therapeutic Development

Novel Pharmacological Approaches:

• Selective sympathetic agonists: To restore function on affected side
• Neuromodulation: Electrical stimulation of sympathetic pathways
• Gene therapy: Future possibility for hereditary forms
• Regenerative medicine: Nerve regeneration strategies^[7]

Minimally Invasive Interventions:

• Radiofrequency ablation: Less invasive alternative to sympathectomy
• Ultrasound-guided procedures: Improved precision in ganglion blocks
• Long-acting local anesthetics: Extended duration blocks^[7]

Conclusion

Harlequin syndrome represents a fascinating disorder of autonomic dysfunction that dramatically illustrates the body’s sympathetic nervous system’s control over thermoregulation and facial appearance. Since Lance’s comprehensive description in 1988, our understanding has evolved from a purely clinical entity to a well-characterized dysautonomic condition with diverse etiologies ranging from idiopathic to iatrogenic causes.

The Mayo Clinic’s recent large case series has significantly advanced our epidemiological and clinical understanding, confirming the condition’s female predominance, typical midlife onset, and generally benign nature. The distinction between primary Harlequin syndrome (without ocular involvement) and Harlequin sign (with associated Horner syndrome) helps guide diagnostic evaluation and prognostication.

The management of Harlequin syndrome reflects the balance between the condition’s benign medical prognosis and its potential for significant psychological impact. While most patients require only reassurance and education, those experiencing severe social embarrassment have treatment options ranging from botulinum toxin injections to surgical sympathectomy, each with distinct risk-benefit profiles.

The key message for healthcare providers is that Harlequin syndrome, while dramatic in appearance, is generally benign and does not require aggressive investigation or treatment unless symptoms are severe or an underlying condition is suspected. A thorough history, neurological examination, and targeted imaging can exclude secondary causes, while autonomic testing confirms the diagnosis and quantifies dysfunction.

For patients, understanding that Harlequin syndrome is not dangerous and typically stable over time provides essential reassurance. The psychological impact should not be minimized, and appropriate support should be offered to those struggling with the cosmetic asymmetry. Treatment decisions should be individualized, weighing the condition’s benign nature against the patient’s psychological distress and treatment risks.

Future research directions include better understanding of pathophysiological mechanisms, development of less invasive treatment options, and improved diagnostic tools. As our knowledge expands, we may identify genetic or environmental risk factors and develop targeted therapies that address the underlying sympathetic dysfunction rather than merely managing symptoms.

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