Probable Tolosa-Hunt syndrome with a normal MRI

Abstract

Background

We are reporting a rare case of a 60-year-old woman with a past history of end-stage renal disease and non-Hodgkin lymphoma who presented to our hospital with confusion, unilateral headache, painful ophthalmoplegia and ptosis. The patient was diagnosed clinically with Tolosa-Hunt syndrome (THS).

Results

THS is a diagnosis of exclusion. Other diseases were ruled out. Magnetic resonance imaging (MRI) of the brain and orbit was negative twice within a week. The patient was treated with corticosteroids with marked improvement of the orbital pain and headache and mild improvement of the cranial nerves palsy.

Conclusion

Clinical diagnosis of THS could be supported by radiological findings. According to the International Classification of Headache Disorders (ICHD)-3 beta diagnostic criteria, the diagnosis must be confirmed with an abnormal MRI and/or pathological sample. We add to the previous findings of THS with a normal MRI. Although MRI plays a crucial role in differential diagnosis, it should not, nor should the biopsy, be a must for the diagnosis. Limitations of using MRI in some patients are another problem.

Introduction

Tolosa-Hunt syndrome (THS) is a rare idiopathic granulomatous inflammatory disease of the cavernous sinus, superior orbital fissure or orbit that causes ocular pain and ophthalmoplegia with prompt response to corticosteroids (1,2). Lack of complete understanding of the pathogenesis of this disease is a barrier for formulation of reliable criteria for its diagnosis. Three editions of International Classification of Headache Disorders (ICHD) diagnostic criteria for THS have been published in 1988, 2004 and 2013 (3–5); in ICHD-3 beta, there have been considerable changes, the validity of which needs to be established.

Case description

A 60-year-old Caucasian woman presented to our hospital with confusion, severe headache and periorbital and retro-orbital pain. Her past history was significant for hypertension, end-stage renal disease on hemodialysis for six years and non-Hodgkin lymphoma diagnosed 15 years ago that was treated with chemotherapy. One week before presentation, she had severe periorbital and retro-orbital pain and right-sided headache. She described the pain as a constant dull, gnawing pain. This was accompanied by nausea and vomiting and deviation of the right eye to the right side with double vision. Three days later, she developed complete ptosis on the right side. The patient presented to the emergency department of another hospital where she had magnetic resonance imaging (MRI) and magnetic resonance angiogram (MRA) of the head and neck with gadolinium that were negative so discharged home with pain medication. She continued to have severe right orbital pain, headache and confusion, so she presented to our hospital. Her physical exam was significant for confusion and distress with photophobia. The patient was unable to answer questions appropriately including mentioning her full name, the day, the month, or the year, but she was able to follow orders when she was asked to raise her hand and try to open her eyes. Vital signs showed a temperature of 37.3℃, blood pressure of 109/82 mmHg, pulse of 109/minute regular, respiratory rate of 21/minute, and oxygen saturation of 98% on room air. Ophthalmic exam revealed right-side complete ptosis and right ophthalmoplegia with deviation of the right eye to the right side. The right pupil was mildly enlarged compared to the left one, but both were reactive to light. There was no conjunctival congestion or hemorrhage and no evidence of orbital trauma. Fundoscopic examination was normal and visual acuity was minimally decreased on the right side. The remainder of the general and neurologic examination was unremarkable. Computed tomography (CT) scan of the head without contrast was performed and was unremarkable. Chest X-ray was normal. Laboratory investigations including complete blood count, glucose, liver and renal functions, fasting blood sugar, vitamin B12, folate, antinuclear antibody (ANA), angiotensin-converting enzyme (ACE), antineutrophil cytoplasmic antibody (c-ANCA), serum protein electrophoresis, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), lupus antibodies, Lyme antibodies, and human immunodeficiency virus (HIV) testing were either normal or negative. Mild hyperphosphatemia and elevated creatinine correlated with end-stage renal disease. Electroencephalography was normal. A repeat MRI of the head and orbit without contrast with coronal and axial T1 spin-echo and T2 turbo spin-echo sequences, T1 fat-suppressed at the orbit and cavernous sinus level was unremarkable with normal cavernous sinuses. Lumbar puncture was performed and the cerebrospinal fluid (CSF) analysis was within normal ranges with normal protein and glucose, negative bacterial, fungal, and mycobacterial cultures, and negative cytology. The patient was diagnosed with THS and was treated with methylprednisolone (4 mg/kg). Forty-eight hours after steroid treatment, the headache and orbital pain markedly improved with mild improvement of the ophthalmoplegia and ptosis (Figures 1 and 2). The patient was discharged home on corticosteroid therapy. Communications with the patient for a follow-up failed multiple times.

Figure 1.

Neuro-ophthalmologic examination of the patient showing right palpebral ptosis.

Figure 2.

Neuro-ophthalmologic examination of the patient showing right palpebral ptosis with exotropia of the primary look of the right eye, paresis of the third, fourth and sixth right cranial nerves.

Discussion

The ICHD-3 beta described THS as unilateral orbital pain associated with paresis of one or more of the third, fourth and/or sixth cranial nerves caused by a granulomatous inflammation in the cavernous sinus, superior orbital fissure or orbit. Neurologic involvement occurs concurrently or begins within two weeks of headache onset (5). Optic nerve dysfunction has been reported, indicating that the pathological process may involve the orbital apex (6). THS is a diagnosis of exclusion and must be differentiated from other causes of painful ophthalmoplegia. Work-up includes detailed history, careful physical examination and routine blood work. Secondary causes should be sought with specific serologic tests, including ACE (sarcoidosis), c-ANCA (Wegener’s granulomatosis), ANA, anti-double-stranded DNA (anti-dsDNA) (lupus), fasting blood sugar, or hemoglobin A1C (diabetes), Lyme antibodies and HIV antibodies. Although the CSF in THS typically is normal, it must be evaluated for infectious and neoplastic causes. Orbital pseudotumor is a related condition of idiopathic inflammation involving the orbit that is distinguished from THS only by a different anatomic localization (7).

In ICHD-3 beta, there have been considerable changes compared to ICHD-I and ICHD-II. One of these changes was strengthening the role of the MRI in the diagnosis of THS. MRI is important for the diagnosis of THS and exclusion of other similar causes such as lymphoma, meningioma and sarcoidosis (8) but THS with a normal MRI was previously reported (8–11). Çakirer (8) reported normal MRI findings in three out of 23 (13%) patients with THS. In a review of the literature; La Mantia et al. (10) reviewed previously reported cases of THS from 1988 to 2002: In 85 patients who fulfilled ICHD-II diagnostic criteria for THS, only 44 (51.8%) had apparent MRI or biopsy evidence of a cavernous sinus granuloma and 41 (48.2%) had no MRI abnormality. They hypothesized that more cases would have been diagnosed with a better imaging protocol. Colnaghi et al. (12) specified the MRI techniques that could reduce the possibility of a false-negative result: 3 mm thickness, coronal and axial T1 spin-echo and T2 turbo spin-echo sequences, T1 fat-suppressed at the orbit and cavernous sinus level. They also emphasized the importance of the MRI as a prognostic factor. In 2013, Zhang et al. (11) reported only 24 out of 46 (52.2%) patients with THS had MRI abnormalities and 22 patients (47.8%) did not. One of the ICHD-3 beta diagnostic criteria of THS is the finding of both granulomatous inflammation of the cavernous sinus, superior orbital fissure or orbit, demonstrated by MRI or biopsy and paresis of one or more of the ipsilateral third, fourth and/or sixth cranial nerves (5). This means that a patient with suspected THS and a negative MRI must have a positive pathological sample for diagnosis. It is clear that the lesions of THS are located in the skull base, inaccessible, close to vital structures and small; therefore, it is not easy to obtain pathological samples. Taking a biopsy from a patient with suspected THS with an excellent response to corticosteroid therapy to confirm the diagnosis should not be needed as it carries a risk of complications. Serial MRI is important to demonstrate complete normalization after medical treatment and confirm no evidence of another etiology (13). Repeat MRI in a patient with an initially normal MRI is also important to demonstrate new inflammatory signs that might appear months after the initial presentation (9). Repeated attempts to contact our patient for a follow-up, for more than two months, failed.

One of the obstacles for serial MRI follow-up is renal failure, which could be a contraindication for administration of gadolinium. This deferred us from exposing our patient to gadolinium for a second time within 48 hours, as this was out of safety concerns and the risk of developing nephrogenic systemic fibrosis outweighed the benefit. The initial MRI and MRA with gadolinium were reviewed by us, and the absence of cavernous sinus pathology was confirmed. Another limitation of MRI is that some neoplastic processes, including central nervous system lymphoma, may appear similar to the unspecific granulomatous inflammation of THS and may even likewise diminish on steroid therapy. Moreover, some of the patients, such as those who have pacemakers, cannot undergo an MRI. In these situations exposing the patients to a risky procedure such as biopsy should not be a must for the diagnosis.

The ICHD-3 beta downgraded the role of glucocorticoids in the diagnosis of THS, but still keeps it in the diagnostic criteria. Our patient had dramatic relief of her pain after 48 hours of initiation of the steroid therapy with minimal improvement of the cranial nerves palsy. This correlates with the findings of Zhang et al. (11), who reported only 60% and 70% resolution of the pain and nerve palsy within 72 hours of initiation of steroid therapy, respectively. Çakirer (8) mentioned that cranial neuropathies tend to recover more slowly over two to eight weeks even with glucocorticoid therapy. THS has a good prognosis but recurrences occur in about 37%–50% of the cases over an interval of months to years (6,11).

We agree with Zhang et al. (11) that ranking the diagnostic criteria and categorizing the diagnosis as definite, probable and possible THS is reasonable and may be helpful to clinicians and researchers, as well as helpful to decrease the financial burden and the complications from unnecessary investigations to confirm the diagnosis.

ICHD-3 has been published in beta version expressly to allow field-testing and revision, as appropriate, before ICHD-3 is finally published in 2015 or 2016.

Clinical implications

Tolosa-Hunt syndrome (THS) is a rare idiopathic inflammatory disease that causes painful ophthalmoplegia. Corticosteroids are the mainstay of the treatment.

Diagnosis of THS is by exclusion and magnetic resonance imaging (MRI) plays a major role in the diagnosis. A negative MRI does not rule out THS; the biopsy role in this situation is questionable.

Renal failure and central nervous system lymphoma might cause limitations of the MRI usage in the diagnosis or follow-up of patients with THS.

International Classification of Headache Disorders (ICHD)-3 beta has major changes compared to the previous editions, the validity of which needs to be studied and established.