Tolosa-Hunt Syndrome

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Background

Tolosa-Hunt syndrome (THS) is a painful ophthalmoplegia caused by nonspecific inflammation of the cavernous sinus or superior orbital fissure. In 2004, the International Headache Society provided a definition of the diagnostic criteria which included granuloma.[1] See the image below.



View Image

MRI of a 40-year-old man with severe periorbital pain ocular sinister (OS; ie, left eye), complete oculomotor nerve palsy OS, and partial abducens ner....

Pathophysiology

Nonspecific inflammation (noncaseating granulomatous or nongranulomatous) within the cavernous sinus or superior orbital fissure is the cause of the constant pain, which characterizes the onset of this disorder. Ophthalmoparesis or disordered eye movements occur when cranial nerves III, IV, and VI are damaged by granulomatous inflammation. Pupillary dysfunction may be present and is related to injury to the sympathetic fibers in the cavernous portion of ICA or parasympathetic fibers that surround the oculomotor nerve. Trigeminal nerve involvement (primarily V1) may cause paresthesias of the forehead. Pathological involvement beyond the cavernous sinus, superior orbital fissure, or apex of the orbit occurs rarely, and the disorder is part of a continuum with idiopathic orbital pseudotumor, with which it shares histopathologic features. Spontaneous remissions can occur; relapses may occur in up to 40% of the patients.

Epidemiology

Frequency

Tolosa-Hunt syndrome (THS) is uncommon in both the United States and internationally. The disorder is rare during the first 2 decades of life; in people older than 20 years, it appears to have an even distribution. When THS occurs in children, the course of the disorder appears to be similar to that experienced by adults.[2] THS affects males and females equally. And, as stated, although rare in children it is important to keep this condition in the differential diagnosis.[32]

Mortality/Morbidity

Tolosa-Hunt syndrome is not a fatal disorder; patients experience unilateral onset of acute orbital pain and ophthalmoparesis, and the disorder may threaten sight if untreated inflammation extends beyond the cavernous sinus to affect the optic nerve.

History

See the list below:

Physical

See the list below:

Causes

The cause of Tolosa-Hunt syndrome is unknown (idiopathic).

Laboratory Studies

The diagnosis of Tolosa-Hunt syndrome is usually one of exclusion.

CBC count, erythrocyte sedimentation rate (ESR), electrolytes with glucose, thyroid function tests, fluorescent treponemal antibody (FTA), antinuclear antibody (ANA), lupus erythematosus (LE) preparation, antineutrophil cytoplasmic antibody (ANCA), serum protein electrophoresis, Lyme titre, angiotensin-converting enzyme (ACE) level, and HIV titre are helpful in eliminating other processes. This level of evaluation is required to exclude other conditions, which can have significant morbidity associated.

Cell count and differential, protein, glucose, fungal and/or bacterial cultures, Gram stain, cytology, and opening pressure of CSF are helpful in eliminating conditions mimicking Tolosa-Hunt syndrome; a mild (lymphocytic) pleocytosis within the spinal fluid may occur in patients with Tolosa-Hunt syndrome.

Anti-GQ1b antibodies may be helpful in distinguishing early, painless Tolosa-Hunt syndrome from Miller Fisher syndrome.

Imaging Studies

MRI[6] of the brain and orbit with and without contrast, magnetic resonance (MR) angiography or digital subtraction angiography (DSA), and CT scan of the brain and orbit with and without contrast may all be useful (see the images below). Inflammatory changes in the cavernous sinus, superior orbital fissure, and/or orbital apex are typically observed on high-resolution contrast-enhanced imaging. In the authors' experience, thin-slice high–magnetic field MRI of the cavernous sinus region, including coronal sections with and without contrast and fat-suppressed cuts of the orbital regions, is the modality of choice. These changes are not specific for Tolosa-Hunt syndrome and may also be present in neoplastic conditions of the cavernous sinus. Enlargement of the optic nerve or external ocular muscles has been described, emphasizing the continuum with idiopathic orbital inflammatory disorders.[31]

Note that findings on all imaging studies may be normal in some cases of Tolosa-Hunt syndrome.

Narrowing of the internal carotid artery within the cavernous sinus may be identified on angiography. Note that these changes are not specific to Tolosa-Hunt syndrome.

MRI with 3-dimensional constructive interference in steady state (3D CISS) provides an enhanced picture within the cavernous sinus. This type of imaging may assist with future diagnoses of TSH, but it is not yet used routinely.[7]



View Image

MRI of a 40-year-old man with severe periorbital pain ocular sinister (OS; ie, left eye), complete oculomotor nerve palsy OS, and partial abducens ner....



View Image

Coronal T1-weighted MRI with (below) and without (above) enhancement demonstrates left cavernous sinus fullness consistent with Tolosa-Hunt syndrome (....

Procedures

Biopsy of the lesion may be required to confirm the diagnosis. The technical difficulty of cavernous sinus region biopsies usually mitigates for a trial of steroids; nonetheless, biopsy may be needed to exclude neoplasm or if symptoms are progressing, atypical, or recurrent.

Histologic Findings

Biopsy reveals nonspecific granulomatous or nongranulomatous inflammation. This is histologically indistinguishable from the pathology of orbital pseudotumor, and these diseases may exist along a continuum.

Medical Care

Corticosteroids are the treatment of choice, usually providing significant pain relief within 24-72 hours of therapy initiation. Ophthalmoparesis usually requires weeks to months for resolution; indeed, ophthalmoparesis may not completely resolve in some cases depending on the degree of inflammation and the aggressiveness of therapy. For refractory cases, azathioprine (Imuran), methotrexate, or radiation therapy[8] has been employed.

Surgical Care

Surgical extirpation is not generally a feasible treatment of Tolosa-Hunt syndrome; the primary value of surgical intervention is a histopathologic diagnosis.

Consultations

Neuro-ophthalmology evaluation is helpful to confirm the diagnosis and to exclude other etiologies of presenting symptoms. Consultation with a neurosurgeon may be useful in cases requiring biopsy.

Medication Summary

Steroids are used to treat the inflammation of Tolosa-Hunt syndrome. Pain relief usually occurs rapidly, ie, within 24-72 hours.[9] Continue treatment at the initial dose for a short time (ie, 7-10 d) after pain resolves, then taper gradually. If no response to steroid therapy has occurred within 72 hours, the diagnosis of Tolosa-Hunt syndrome should be reevaluated.

If a patient is unable to tolerate steroid therapy, other immunosuppressive therapy may be considered.

Prednisone (Sterapred)

Clinical Context:  May decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. Stabilizes lysosomal membranes and also suppresses lymphocytes and antibody production.

Class Summary

Reduce pain and inflammation; diminish the size of the inflammatory mass.

Methotrexate (Trexall)

Clinical Context:  Antimetabolite used to treat many autoimmune processes. The mode of action is not known; this drug does interfere with DNA synthesis.

Azathioprine (Imuran)

Clinical Context:  Immunosuppressive agent that works primarily on T cells. Works very slowly; may require 6-12 mo of trial prior to effect. Up to 10% of patients may have idiosyncratic reaction disallowing use. Do not allow WBC count to drop below 3000/µL or lymphocyte count to drop below 1000/µL.

Class Summary

Decrease autoimmune reaction.

Further Outpatient Care

Supervise a tapering schedule for the steroids and monitor for steroid-related adverse effects. Because the diagnosis of Tolosa-Hunt syndrome is often made clinically without histopathologic confirmation, vigilance must be maintained for the possibility of alternative masquerading diagnosis.

Complications

See the list below:

Prognosis

See the list below:

Patient Education

See the list below:

What is Tolosa-Hunt syndrome (THS)?What is the pathophysiology of Tolosa-Hunt syndrome (THS)?What is the prevalence of Tolosa-Hunt syndrome (THS)?What is the morbidity associated with Tolosa-Hunt syndrome (THS)?Which clinical history findings are characteristic of Tolosa-Hunt syndrome (THS)?Which physical findings are characteristic of Tolosa-Hunt syndrome (THS)?What causes Tolosa-Hunt syndrome (THS)?What are the differential diagnoses for Tolosa-Hunt Syndrome?What is the role of lab tests in the workup of Tolosa-Hunt syndrome (THS)?What is the role of imaging studies in the workup of Tolosa-Hunt syndrome (THS)?What is the role of biopsy in the workup of Tolosa-Hunt syndrome (THS)?Which histologic findings are characteristic of Tolosa-Hunt syndrome (THS)?How is Tolosa-Hunt syndrome (THS) treated?What is the role of surgery in the treatment of Tolosa-Hunt syndrome (THS)?Which specialist consultations are beneficial to patients with Tolosa-Hunt syndrome (THS)?What is the role of steroids in the treatment of Tolosa-Hunt syndrome (THS)?Which medications in the drug class Immunosuppressive agents are used in the treatment of Tolosa-Hunt Syndrome?Which medications in the drug class Corticosteroids are used in the treatment of Tolosa-Hunt Syndrome?What is included in long-term monitoring of Tolosa-Hunt syndrome (THS)?What are the possible complications of Tolosa-Hunt syndrome (THS) treatment?What is the prognosis of Tolosa-Hunt syndrome (THS)?What is included in patient education about Tolosa-Hunt syndrome (THS)?

Author

Danette C Taylor, DO, MS, FACN, Service Chief of Neurology, Henry Ford West Bloomfield Hospital; Senior Staff Neurologist, Henry Ford Health Systems; Clinical Assistant Professor, Department of Neurology and Ophthalmology, Michigan State University College of Osteopathic Medicine

Disclosure: Nothing to disclose.

Specialty Editors

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Nicholas Lorenzo, MD, MHA, CPE, Co-Founder and Former Chief Publishing Officer, eMedicine and eMedicine Health, Founding Editor-in-Chief, eMedicine Neurology; Founder and Former Chairman and CEO, Pearlsreview; Founder and CEO/CMO, PHLT Consultants; Chief Medical Officer, MeMD Inc; Chief Strategy Officer, Discourse LLC

Disclosure: Nothing to disclose.

Chief Editor

Tarakad S Ramachandran, MBBS, MBA, MPH, FAAN, FACP, FAHA, FRCP, FRCPC, FRS, LRCP, MRCP, MRCS, Professor Emeritus of Neurology and Psychiatry, Clinical Professor of Medicine, Clinical Professor of Family Medicine, Clinical Professor of Neurosurgery, State University of New York Upstate Medical University; Neuroscience Director, Department of Neurology, Crouse Irving Memorial Hospital

Disclosure: Nothing to disclose.

Additional Contributors

Eric R Eggenberger, DO, MS, FAAN, Professor, Vice-Chairman, Department of Neurology and Ophthalmology, Colleges of Osteopathic Medicine and Human Medicine, Michigan State University; Director of Michigan State University Ocular Motility Laboratory; Director of National Multiple Sclerosis Society Clinic, Michigan State University College of Human Medicine

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: LifeBlood<br/>Serve(d) as a speaker or a member of a speakers bureau for: Biogen; Genzyme; Novartis; Teva; Mallinckrodt<br/>Received research grant from: Biogen; Genzyme; Novartis<br/>Received consulting fee from Biogen for consulting; Received consulting fee from Teva for consulting; Received consulting fee from Acorda for consulting; Received grant/research funds from Novartis for independent contractor; Received honoraria from Genentech for speaking and teaching; Received honoraria from Genzyme for speaking and teaching.

Florian P Thomas, MD, PhD, MA, MS, Chair, Neuroscience Institute and Department of Neurology, Director, National MS Society Multiple Sclerosis Center and Hereditary Neuropathy Foundation Center of Excellence, Hackensack University Medical Center; Founding Chair and Professor, Department of Neurology, Hackensack Meridian School of Medicine at Seton Hall University; Professor Emeritus, Department of Neurology, St Louis University School of Medicine; Editor-in-Chief, Journal of Spinal Cord Medicine

Disclosure: Nothing to disclose.

Acknowledgements

The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous author Kenneth A Mankowski, DO to the development and writing of this article.

References

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MRI of a 40-year-old man with severe periorbital pain ocular sinister (OS; ie, left eye), complete oculomotor nerve palsy OS, and partial abducens nerve palsy OS. Axial imaging without (left) and with (right) enhancement demonstrates nonspecific fullness involving the left cavernous sinus, consistent with Tolosa-Hunt syndrome within the context of the history. Treatment with steroids produced complete resolution of symptoms. Image courtesy of Eric Eggenberger, DO.

MRI of a 40-year-old man with severe periorbital pain ocular sinister (OS; ie, left eye), complete oculomotor nerve palsy OS, and partial abducens nerve palsy OS. Axial imaging without (left) and with (right) enhancement demonstrates nonspecific fullness involving the left cavernous sinus, consistent with Tolosa-Hunt syndrome within the context of the history. Treatment with steroids produced complete resolution of symptoms. Image courtesy of Eric Eggenberger, DO.

Coronal T1-weighted MRI with (below) and without (above) enhancement demonstrates left cavernous sinus fullness consistent with Tolosa-Hunt syndrome (THS). The imaging features are nonspecific and must be placed into the context of the history, examination, and clinical course to avoid misdiagnosis of infiltrating, infectious, or neoplastic cavernous sinus processes. Image courtesy of Eric Eggenberger, DO.

MRI of a 40-year-old man with severe periorbital pain ocular sinister (OS; ie, left eye), complete oculomotor nerve palsy OS, and partial abducens nerve palsy OS. Axial imaging without (left) and with (right) enhancement demonstrates nonspecific fullness involving the left cavernous sinus, consistent with Tolosa-Hunt syndrome within the context of the history. Treatment with steroids produced complete resolution of symptoms. Image courtesy of Eric Eggenberger, DO.

Coronal T1-weighted MRI with (below) and without (above) enhancement demonstrates left cavernous sinus fullness consistent with Tolosa-Hunt syndrome (THS). The imaging features are nonspecific and must be placed into the context of the history, examination, and clinical course to avoid misdiagnosis of infiltrating, infectious, or neoplastic cavernous sinus processes. Image courtesy of Eric Eggenberger, DO.