Complete ophthalmoplegia diagnosed as Tolosa-Hunt syndrome on interval MRI
- 1 School of Medicine, Western University of Health Sciences College of Osteopathic Medicine of the Pacific-Northwest, Lebanon, Oregon, USA
- 2 Department of Radiology, Oregon Health and Science University, Portland, Oregon, USA
- Correspondence to Dr Andrew Helming; helming@ohsu.edu
Abstract
Tolosa-Hunt syndrome is a rare cause of painful ophthalmoplegia, most commonly presenting with retro-orbital pain and eye motor nerve palsy, most often affecting a single eye. The condition is characterised by an idiopathic process causing granulomatous inflammation to the cavernous sinus affecting, one or multiple cranial nerves that pass therein. The mechanism underlying the inflammation is not well understood, but patients have been observed to respond to steroids during a flare. We present this as a unique case where a multidisciplinary team diagnosed Tolosa-Hunt syndrome despite non-specific MRI findings in the cavernous sinus 1 day following an initially normal MRI.
Background
With an annual incidence of between one and two cases in a million, Tolosa-Hunt syndrome is a rare cause of painful ophthalmoplegia affecting men and women of all ages.1 Patients typically present with retro-orbital pain and eye motor nerve palsy, most often affecting a single eye. The condition is characterised by an idiopathic process causing granulomatous inflammation to the cavernous sinus affecting one or multiple of the CN nerves that traverse the space: III, IV, VI, as well as occasionally the sensory nerves V1 and V2. The rare incidence of Tolosa-Hunt syndrome and the low number of biopsied lesions have contributed to a poor understanding of the underlying mechanism. Responsiveness to steroids is considered a key feature of the condition, and it has been historically regarded as a differentiating feature from similar syndromes.2 3 With a pattern of presentation nearly identical to other causes of cavernous sinus syndrome, it is critical to evaluate for other causes prior to initiating treatment. Literature frequently describes tumours and other inflammatory processes masquerading as Tolosa-Hunt syndrome with normal imaging findings, medical evaluation and improvement with steroids.4 One study of 73 patients with cavernous sinus syndrome found that the underlying aetiology could only be definitively diagnosed in 86% of cases. Tolosa-Hunt syndrome represented 23.2% of these cases, with neoplastic and fungal causes each being more prevalent.5 Therefore, diagnostic recommendations advise ruling out other disease processes prior to solidifying the diagnosis and initiating therapy, as steroids may not be indicated. To guide diagnosis, the Headache Classification Committee of the International Headache Society (IHS) wrote the International Classification of Headache Disorders in 2018, which provided an update to the previous Tolosa-Hunt diagnostic criteria from 2003. These criteria could be summarised as an ophthalmoplegia preceded by or simultaneously occurring with an ipsilateral headache, MRI or biopsy with granulomatous inflammation in the cavernous sinus, superior orbital fissure or orbit, as well as no alternate diagnosis being more likely.2 Conversely, there is debate regarding the obligatory imaging or biopsy findings, as imaging findings are not present in all cases, and biopsy is highly invasive.6 Our case demonstrates the value of interval imaging when a patient did not initially meet the Tolosa-Hunt diagnostic criteria.
Case presentation
A woman in her 60s with a history of hypothyroidism presented with progressively worsening diplopia, L eye ptosis and pain starting suddenly 2 weeks before presentation. She was seen by ophthalmology the day after symptoms began and diagnosed with a left CN VI palsy. Symptoms progressed to complete ptosis in the ensuing 2 weeks as she awaited an outpatient MRI of her brain. Following the MRI, she presented to the emergency department given the onset of complete left eye ophthalmoplegia and was admitted for further workup. Her eyelid was completely shut over a fixed eye in the central position. In ambient light, the left pupil was slightly larger than the right at 4 mm. The left pupil was unreactive to light in either eye. However, the right pupil contracted appropriately with left afferent limb stimulation. Visual fields were full of confrontation. She denied any blurry vision in the left eye or sensory deficits in the face. Vital signs were within normal limits, and further examination was unremarkable.
Investigations
The MRI obtained outpatient, in addition to a CTA (computed tomography angiogram) obtained on admission, was unrevealing. A complete blood count, blood metabolic panel, erythrocyte sedimentation rate and C reactive protein were all within normal limits. Neurology advised additional testing with TSH (thyroid-stimulating hormone), B12, MMA (methylmalonic acid), folate, B1, ACE (angiotensin-converting enzyme), ANA (antinuclear antibody, anti-dsDNA (anti-double stranded DNA), anti-Smith, anti-RNP (ribonucleoprotein)/Smith, ANCA (antineutrophil cytoplasmic antibodies), Borrelia, treponemal antibody and protein electrophoresis, all of which was negative. A1C was noted to be 6.0. Ophthalmology recommended an additional MRI of the orbits and brain, which produced T1 imaging showing mild asymmetric enlargement of the left cavernous sinus compared with the right side, with a focal area of signal characteristics and enhancement postcontrast administration slightly different than the adjacent sinus measuring 10×11×6 mm (figure 1).
Lesion identified by the white arrow on T1-weighted postgadolinium-based contrast axial (A) and coronal (B) MRI of the brain and orbits showing hyperintense enhancing convexity protruding from the medial wall of the left cavernous sinus.
Differential diagnosis
The initial differential diagnosis was comprehensive. Vasculitis, meningitis, sarcoidosis, tuberculosis, other infectious process, neoplasia, thyroid ophthalmopathy and diabetic ophthalmoplegia were all considered. Due to the patient’s underlying chronic conditions, thyroid ophthalmopathy and diabetic ophthalmoplegia were given primary consideration. However, TSH was within normal limits, which made thyroid-related ophthalmoplegia less likely. Diabetic ophthalmoplegia would be atypical, with the presence of a marked polyneuropathy with pupillary involvement. Given normal inflammatory markers, a systemic inflammatory condition such as vasculitis was thought to be less likely. Furthermore, given negative ANA, anti-dsDNA, anti-Smith and anti-RNP/Smith, a rheumatological disease was of low clinical suspicion. Borrelia and treponemal antibody titres were negative, which lowered suspicion of infectious aetiology in conjunction with the patient being low risk. Pertinently, the patient had a recently negative QuantiFERON Gold as well. Negative protein electrophoresis made gammopathy or amyloidosis less likely.
Based on the subsequent neuroimaging showing an enhancing hyperintense convex lesion in the cavernous sinus, the differential diagnosis included Tolosa-Hunt syndrome, meningioma, sarcoidosis or lymphoma. Consultation with neurology and neurosurgery concluded that the appearance, rapid onset and clinical course with pain were most representative of Tolosa-Hunt syndrome. Meningioma would likely be painless and progress over months to involve multiple cranial nerves. Negative ACE testing lowered clinical suspicion of sarcoidosis. No aberrations of the serum cell differential or systemic symptoms suggested lymphoma. The overall presentation met the Tolosa-Hunt diagnostic criteria, as other pathologies potentially causative of painful ophthalmoplegia were sufficiently evaluated.
Treatment, outcome and follow-up
The patient started treatment with 40 mg prednisone for 3 days and within 24 hours had resolution of pain. Ptosis and extraocular movements with all ocular motor nerves dramatically improved as well. The efferent pupillary action returned and responded to stimulation of both optic nerve afferent limbs. Additional studies were completed with chest X-ray and lumbar puncture studies, yielding negative results. At this point, it was recognised that the patient would not benefit from further inpatient evaluation. She was discharged with outpatient neurology and ophthalmology follow-up appointments.
Discussion
Initially recognised by a Spanish neurosurgeon in the 1950s, and eponymously dubbed ‘Tolosa-Hunt syndrome’ by Hunt et al, this entity is characterised by painful ophthalmoplegia associated with a preceding ipsilateral headache. It is caused by inflammation within the enclosed space of the cavernous sinus with resultant cranial nerve compression and oculomotor deficits.3 The causative inflammation is often idiopathic but can be traumatic, neoplastic or aneurysmal in aetiology. Though Tolosa-Hunt syndrome is inflammatory and has been reported in conjunction with SLE, other autoimmune diseases, trauma and pregnancy, it is not associated with systemic inflammation.7
MRI is the most useful diagnostic technique for identifying Tolosa-Hunt syndrome. Other cross-sectional imaging, namely CT, is less specific as the lesions may be harder to visualise.8 MRI findings according to the ICH criteria show granulomatous inflammation; however, imaging abnormalities are non-specific and not present in all cases. Studies from 1989 and 2014 found pathological imaging findings in 9 of 11 and 20 of 21 patients examined, respectively.9 10 General findings include a contrast enhancing space-occupying lesion to be isointense to muscle on T1 and isointense or hypointense to fat on T2 with a majority of these lesions originating from the medial wall and protruding out in a convex shape.9 Despite biopsy being used as a diagnostic criterion in the absence of imaging findings, few cases of Tolosa-Hunt syndrome receive a neurosurgical intervention. Prompt steroid treatment of granulomatous MRI findings further decreases the utility of biopsy, as abnormality may improve and biopsy non-diagnostic. In cases where a biopsy was not initially taken, researchers recommend MRI every 3–4 weeks to monitor clinical progression.1 A recent case report from 2022 identified potential in arterial spin latency MRI improving the diagnosis and monitoring of Tolosa-Hunt syndrome after steroid therapy.11 Until further research identifies and validates new imaging techniques, MRI with contrast will remain the greatest tool in the evaluation of painful ophthalmoplegia, despite its limitations.
Typical histopathology of Tolosa-Hunt syndrome includes non-specific granulomatous findings primarily composed of fibrosis and lymphocytes.9 No study has identified pathognomonic characteristics for Tolosa-Hunt syndrome, further introducing diagnostic uncertainty. Biopsies are reserved for those in which diagnostic labs are equivocal and in whom there is clinical concern for an occult process that could not otherwise be ruled out. An example, a 2013 case report details a patient receiving a biopsy for painful ophthalmoplegia following positive tuberculosis QuantiFERON. Biopsy, in this case, did not show a tuberculoma, but Tolosa-Hunt syndrome was diagnosed after pathology showed fibrosis, inflammatory cells and degenerative cells. Uniquely, the findings suggested a chronic local inflammatory tissue change, yet the patient did improve with steroids.12 A more recent example in literature is a case notable for intraparenchymal extension on imaging, where biopsy of the cavernous sinus demonstrated tissue with fibrous changes and lymphocyte infiltration.13 Improvement with medical treatment has not been validated as evidence supporting a Tolosa-Hunt diagnosis, as other inflammatory, infectious, or neoplastic processes notably resolve with steroids.4 Additionally, cases of Tolosa-Hunt syndrome have been documented as steroid-resistant.8
Our patient did not initially meet the IHS criteria for Tolosa-Hunt syndrome when the first MRI did not show any lesion in the cavernous sinus space, despite a clinical exam suggesting nerve impairment isolated to this anatomic region. The literature is sparse and does not provide established guidelines regarding the evaluation of similar patients. Biopsy of the cavernous space was considered; however, there was a low suspicion for alternative processes with reassuring clinical history and laboratory studies. MRI findings a day following a normal investigation solidified Tolosa-Hunt syndrome as a primary cause of symptoms and supported the decision to start steroids. We recommend that in cases where imaging findings and serology studies are negative, repeat imaging should be considered prior to biopsy or initiation of treatment.
Learning points
-
There is a high risk of misdiagnosis in Tolosa-Hunt syndrome, and interval imaging may be required to identify an abnormality correlating with the clinical examination.
-
A broad differential should be considered and evaluated prior to initiating steroid treatment.
-
It is crucial that the history of disease progression according to the International Headache Society criteria supports the diagnosis, as pathology and imaging findings are notably non-specific.
Ethics statements
Patient consent for publication
Acknowledgments
The authors would like to acknowledge the involved neurology, neurosurgery, and neuroradiology teams for their assistance in making this complex diagnosis.
Footnotes
-
Contributors SB and AH conception, organisation, drafting and revising.
-
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
-
Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.
-
Competing interests None declared.
-
Provenance and peer review Not commissioned; externally peer reviewed.
- © BMJ Publishing Group Limited 2022. No commercial re-use. See rights and permissions. Published by BMJ.
References
Use of this content is subject to our disclaimer