Tolosa-Hunt Syndrome

THS patients typically present with severe orbital and periorbital pain of acute onset that may exacerbate in episodes. Without appropriate treatment, this pain does not subside and persists for weeks. It coincides with ophthalmoplegia, i.e., cranial nerve palsies indicating lesions of the oculomotor, trochlear and/or abducens nerves (limited eye movement, mydriasis, lacking accomodation and ptosis). A delay of several days between onset of pain and ophthalmoplegia has been observed in some cases. Additionally, patients may report paresthesias in the upper face. The corneal reflex may be disturbed. These symptoms are due to compression of the ophthalmic and maxillary branches of the trigeminal nerve. These symptoms are observed unilaterally and usually, no disturbances can be detected on the contralateral side. Reports about bilateral THS are very rare.

Despite ophthalmoplegia, vision is often not disturbed. Some patients experience diplopia. Vision loss is associated with damage to the optical nerve and thus with extensive inflammation. Visual impairment is not characteristic for THS limited to the cavernous sinus.

Orbital and periorbital pain should resolve within very few days after initiation of corticosteroid therapy. If this is not the case, a thorough re-examination should take place to detect possible alterations that might have been overlooked the first time. Although proof of granulomatous inflammation of the cavernous sinus, either by histopathological analysis of biopsy samples or by magnetic resonance imaging, rises a strong suspicion for THS, there is no pathognomonic symptom for this syndrome. In fact, THS mimics a variety of other, possibly much more severe conditions and its diagnosis is based on ruling out the latter. If any hint as to one of those other diseases is missed, a patient may be erroneously be diagnosed with THS. On the other hand, THS may not be recognized for what it is [9]. In such cases, initiation of the rather simple but effective treatment may unnecessarily be delayed and the risk for further neurological damage increases.

While periorbital pain and ophthalmoplegia may be recognized in anamnesis and clinical examination, respectively, neuroimaging is necessary to detect inflammation of the cavernous sinus. Magnetic resonance imaging is the technique of choice. But although evidence for a granulomatous inflammation is mandatory to diagnose THS, negative findings leave doubts in about 50% of all THS patients. If no signs for inflammation can be observed and the suspicion for THS persists, a biopsy should be taken. If pathohistological analysis of biopsy samples does neither indicate granulomatous inflammation, the patient does not fulfill the diagnostic criteria for THS. Here, further diagnostic imaging, e.g., computed tomography scans and angiography, are recommended to identify the cause of headaches and ophthalmoplegia.

Diagnostic treatment with corticosteroids is reasonable if neuroimaging did not reveal any alterations that require urgent attention. Corticosteroid therapy should significantly improve the patient's condition within a maximum of 72 hours, probably even less.

According to diagnostic criteria published by the International Headache Society in 2004, ruling out differential diagnoses is essential for diagnosing THS. In this context, differential diagnoses to be considered are:

• Cavernous sinus thrombosis
• Carotid-cavernous fistula
• Aneurysm of the internal carotid artery
• Hemorrhage due to trauma or hemorrhagic infarction
• Neoplasm
• Sarcoidosis
• Wegener granulomatosis

Some of these conditions are life-threatening but may nevertheless be missed during first examination. In order to compensate for possible erroneous diagnoses, any patient diagnosed with THS should undergo annual or at least biannual follow-ups. As a part of these exams, magnetic resonance imaging should be repeated.

Prolonged oral administration of corticosteroids is the treatment of choice. While according to diagnostic criteria, patients should respond within 72 hours to such therapy, most individuals suffering from THS do so within 24 hours. Pain should considerably subside in this time frame, but ophthalmoplegia may persist for several more weeks. In some cases, neuronal damage is partially permanent.

Treatment is initiated with high-dose corticosteroids, but upon response to therapy the patient's dose may be reduced. Success of therapy should be controlled with regular magnetic resonance imaging. Such examinations should be done every one or two months until lesions are no longer detectable [10].

Failure to respond to therapy strongly suggests an alternative diagnosis. If no hints at any of the above mentioned differential diagnoses can be found and refractory THS is suspected, immunosuppression may be achieved with azathioprine, methotrexate or radiation therapy [11].

There is no surgical treatment for THS. Any surgical intervention realized in THS patients primarily fulfills diagnostic functions.

THS patients usually respond well to systemic corticosteroid therapy, most likely within 24 hours [8]. If that is not the case, differential diagnoses should be re-considered. Moreover, relapses are common and require prolonged immunosuppressive treatment.

Complications include persisting cranial nerve palsies. These may affect eye movements or, in more severe cases where the inflammation spread, vision.

The precise cause of THS is still unknown. Patients present a granulomatous inflammation of the cavernous sinus, sometimes also of the superior orbital fissure. Due to it being a space-occupying pathological process, it may compress adjacent tissues such as cranial nerves passing through the walls of the above mentioned sinus. The inflammation may also spread to these nerves and thereby impair their function. The granulomatous inflammation may possibly be triggered by an autoimmune response, although this theory requires further corroboration. Indeed, THS has been described in a patient suffering from systemic lupus erythematodes, but this may merely be a coincidence [5]. Vascular alterations are another possible cause of cavernous sinus inflammation.

THS is a rare neurological syndrome. The annual incidence has been estimated to be 1-2 per 1,000,000 individuals [6].

With regards to age, THS is less frequently diagnosed in children and adolescents. Adults of any age seem to be affected equally. Neither pathophysiological nor clinical differences have been observed regarding disease progress in pediatric, adolescent and adult patients, but this may be due to the restricted case number of younger patients [7].

No predilections regarding gender or race have been described.

THS-associated morbidity depends on timing of diagnosis and initiation of treatment. If left untreated, the inflammation may spread, compromise additional cranial nerves and cause vision loss. No fatalities have been reported related to THS.

THS is caused by a granulomatous inflammation of the cavernous sinus and possibly of the superior orbital fissure. Histopathological analyses have shown giant-cell granuloma, lymphocyte infiltration and fibroblast proliferation, the latter presumably representing repair processes, in the wall of the dural sinus [1] [2]. Up to date, no evidence for involvement of infectious agents has been found and granuloma are apparently sterile. Nevertheless, they exert considerable pressure on surrounding tissues, namely those cranial nerves passing through the wall of the cavernous sinus.

Since oculomotor, trochlear and abducens nerves contain the vast majority of motor nerve fibers controlling movements of the ocular globe, pupils and eyelids, damage of these nerves results in ophthalmoplegia. The ophthalmic and maxillary branches of the trigeminal nerve mainly contain somatosensory fibers. If they are affected by cavernous sinus syndromes, sensory loss occurs in the area supplied by these nerves.

If the inflammation spreads any further, other tissues may be compromised [6].

No preventive measures can be recommended.

The cavernous sinus is delimited by endothelial-lined dura mater, is located lateral to the sella turcica and borders temporal and sphenoid bones. Of clinical importance is its close proximity to cranial nerves III (oculomotor nerve), IV (trochlear nerve), V (trigeminal nerve) and VI (abducens nerve) as well as the internal carotid artery. These cranial nerves may be affected by space-occupying processes such as aneurysms or neoplasms and may be compressed. This type of disorder is termed cavernous sinus syndrome. According to its respective etiology, different cavernous sinus syndromes may be classified further. Tolosa-Hunt syndrome (THS) is a cavernous sinus syndrome of unknown etiology.

THS has first been described in 1954 by Eduardo Tolosa and William Edward Hunt [1] [2]. Diagnostic criteria for THS have last been published in 2004, 50 years later [3] and include a granulomatous inflammation of the cavernous sinus. While such an inflammation may serve as an explanation for symptoms characteristically associated with THS, it is still deemed idiopathic. THS is most frequently unilateral and symptoms are observed ipsilaterally. Typical symptoms comprise headaches, periorbital pain, ophthalmoplegia and sometimes additional neurologic deficits, particularly facial sensory loss. The latter may be caused by damage to the ophthalmic and maxillary branches of the trigeminal nerve. THS patients do not necessarily present the complete spectrum of cranial nerve palsies associated with cavernous sinus syndromes but may rather show any combination thereof.

Patients generally respond well to anti-inflammatory medication in form of corticosteroids. Many THS patients suffer from relapses and require prolonged immunosuppressive treatment. The medical challenge consists in diagnosing THS and effectively distinguishing this syndrome from other, more severe pathologies, e.g. aneurysm, thrombosis, neoplasm and trauma. To date, diagnosis of THS is mainly a diagnosis of exclusion [4].

Tolosa-Hunt syndrome (THS) is a rare disorder associated with headaches, particularly in close proximity to one of the eyes, and the inability to perform certain eye movements.

Causes

Eye movements are controlled by three cranial nerves, namely the oculomotor, trochlear and abducens nerves. They arise from the brain stem and pass through distinct parts of the brain until reaching their target structures. All these nerves pass alongside an enlarged blood bag called the cavernous sinus. In addition to the above mentioned nerves, a sensory cranial nerve named trigeminal nerve and the internal carotid artery also pass the cavernous sinus.

An inflammation or any space-occupying process affecting the cavernous sinus results in compression and subsequent functional impairment of the cranial nerves that cross its wall.

Symptoms

In THS, a granulomatous inflammation of as of yet unknown etiology affects the cavernous sinus. The inflammation itself causes pain that may not subside during weeks if appropriate treatment is not provided. As has been described before, this inflammation results in cranial nerve damage. THS patients do not necessarily present paresis of all cranial nerves crossing the cavernous sinus, but may be unable to move their eye globes and their eyelids. Accommodation, i.e., focusing on near or far objects, and pupillary constriction may be blunted.

If the trigeminal nerve is affected, the patient may experience abnormal sensations in their upper face.

Vision loss is not characteristic for THS. However, the inflammation may spread from the cavernous sinus to adjacent tissues, may damage yet another cranial nerve, the optical nerve, and in these cases, vision loss is possible.

Diagnosis

Medical history and clinical examination may prompt a suspicion for THS, but neuroimaging needs to be carried out in order to identify the granulomatous inflammation that affects the cavernous sinus. This is usually done with magnetic resonance imaging. If no alterations can be detected, a small tissue sample will be obtained and histopathologically analyzed. It is of utmost importance to verify if there is a granulomatous inflammation because THS may mimic a variety of other, possibly much more severe conditions that need to be ruled out. If any doubts remain as to the presence of vascular anomalies, thrombosis or a tumor, additional diagnostic imaging will be realized.

Patients diagnosed with THS should undergo regular follow-ups to verify that significant lesions were not missed during first examination.

Treatment

Therapy aims at relieving pain and reducing the inflammation. Prolonged oral administration of corticosteroids is the method of choice. Most THS patients respond to such treatment within one day, possibly within two or three. Pain should subside shortly after initiation of treatment, but neurologic damage may take weeks or even months to resolve. In rare cases, neurological deficits are partially permanent.

During therapy, patients will undergo regular examinations with magnetic resonance imaging in order to verify if intracranial lesions resolve as well as pain and nerve palsies.

1. Tolosa E. Periarteritic lesions of the carotid siphon with the clinical features of a carotid infraclinoidal aneurysm. J Neurol Neurosurg Psychiatry. 1954; 17(4):300-302.
2. Hunt WE, Meagher JN, Lefever HE, Zeman W. Painful opthalmoplegia. Its relation to indolent inflammation of the carvernous sinus. Neurology. 1961; 11:56-62.
3. La Mantia L, Curone M, Rapoport AM, Bussone G. Tolosa-Hunt syndrome: critical literature review based on IHS 2004 criteria. Cephalalgia. 2006; 26(7):772-781.
4. Arshad A, Nabi S, Panhwar MS, Rahil A. Tolosa-Hunt syndrome: an arcane pathology of cavernous venous sinus. BMJ Case Rep. 2015; 2015.
5. Calistri V, Mostardini C, Pantano P, Pierallini A, Colonnese C, Caramia F. Tolosa-Hunt syndrome in a patient with systemic lupus erythematosus. Eur Radiol. 2002; 12(2):341-344.
6. Iaconetta G, Stella L, Esposito M, Cappabianca P. Tolosa-Hunt syndrome extending in the cerebello-pontine angle. Cephalalgia. 2005; 25(9):746-750.
7. Zanus C, Furlan C, Costa P, Cosentini D, Carrozzi M. The Tolosa-Hunt syndrome in children: a case report. Cephalalgia. 2009; 29(11):1232-1237.
8. Zurawski J, Akhondi H. Tolosa-Hunt syndrome--a rare cause of headache and ophthalmoplegia. Lancet. 2013; 382(9895):912.
9. Lachanas VA, Karatzias GT, Tsitiridis I, Panaras I, Sandris VG. Tolosa-Hunt syndrome misdiagnosed as sinusitis complication. J Laryngol Otol. 2008; 122(1):97-99.
10. Cakirer S. MRI findings in Tolosa-Hunt syndrome before and after systemic corticosteroid therapy. Eur J Radiol. 2003; 45(2):83-90.
11. Foubert-Samier A, Sibon I, Maire JP, Tison F. Long-term cure of Tolosa-Hunt syndrome after low-dose focal radiotherapy. Headache. 2005; 45(4):389-391.