Tolosa-Hunt syndrome presenting with features of a trigeminal autonomic cephalalgias and pituitary enlargement

Abstract

Tolosa-Hunt syndrome is understood as a steroid-responsive, relapsing-remitting, unilateral headache disorder associated with ipsilateral cranial neuropathies, of a probable granulomatous aetiology. The diagnosis is made clinically from the history and examination, supported by appropriate imaging. Here the authors report a case of Tolosa-Hunt syndrome with a headache phenotype mimicking a trigeminal autonomic cephalalgias (hemicrania continua), and serial MRI studies showing a stable enlarged pituitary. Due to her initial lack of clinical signs, she was diagnosed with chronic migraine, revised to hemicrania continua based on indomethacin response, then revised back to chronic migraine. Her final diagnosis was achieved after she developed a left cavernous sinus syndrome 4 years into her disease course. This case shows that Tolosa-Hunt syndrome may present with a non-side-locked headache and delayed development of clinical signs. Clinicians should also maintain a high degree of suspicion when faced with incidental MRI findings.

Background

Tolosa-Hunt syndrome is understood as a relapsing-remitting unilateral headache disorder associated with ipsilateral cranial neuropathies.^{1 2} Its symptoms typically span weeks, can be self-limiting and responds markedly to steroids.^{1 2} The true aetiology remains unknown but granulomatous inflammation has been found at postmortem in a single case.¹

Case presentation

A woman in her 40s with previous pregnancy-related migraines presented to the neurology outpatient clinic in for a 3-month history of gradual-onset chronic daily headache. Her headaches were of moderate intensity. They lateralised to her right face, where she described stabbing pains that extended retro-orbitally without autonomic features. She sometimes experienced blurred vision, but had no vision loss and no visual auras. There was no nausea, vomiting, photophobia or phonophobia at the time. Simple over-the-counter analgesia did not help. She had a normal neurological examination. A plain CT study of her head was normal. Given her normal examination and screening investigations, she was diagnosed with probable migraine without aura. The duration of her symptoms further led to a diagnosis of probable chronic migraine without aura. She was advised to try nortryptiline. Her symptoms did not improve with this, so she was switched to topiramate.

Four months later, she developed a slight right-sided ptosis with lacrimation of the right eye, without conjunctival injection. She was now also nauseated with the headaches, which remained lateralised to the right side. She had noticed that naproxen was effective at controlling her headache, but she had to discontinue this due to gastric upset. She was advised to try indomethacin 25 mg three times a day, which gave her relief from her headache. Her working diagnosis was therefore revised to hemicrania continua based on her headache duration, autonomic features, side-locked headache and response to indomethacin. In addition to indomethacin, her headache prophylaxis medication was changed from topiramate 25 mg once a day to gabapentin. This successfully controlled her headache.

Given the persistence of her headaches, an MRI study of her head was arranged. This showed a mildly enlarged pituitary gland, and a referral to the pituitary multidisciplinary team was made. The appearances were felt to be concordant with an incidental pituitary macroadenoma. Her serum pituitary profile was normal, and the pituitary multidisciplinary team started ongoing radiological surveillance.

Unfortunately, after staying on indomethacin for 2 weeks, she had to discontinue it due to more gastrointestinal side effects. Her headaches remained well controlled for a month after the discontinuation of indomethacin. She then went on to suffer a relapse of her symptoms.

Her headaches persisted as a chronic daily headache for 2 years. She was treated with verapamil, occipital nerve blocks, and sodium valproate to no effect. She tried acupuncture privately and her headache symptoms improved. She had a pain-free period of approximately half a year by the time she attended neurology clinic again, 3 years after her initial presentation.

Eight months after that, she developed a new left-sided orbital headache which extended to the occiput. The headache was present daily, constant throughout the day and described as crushing and burning in nature with significant diurnal variation. The pain was worse in the morning on waking and in the evening but there was no positional association. She also suffered from fatigue and nausea. This headache differed from the previous right-sided headache as there were no associated autonomic features of ptosis, epiphora or conjunctival injection. The diagnosis of hemicrania continua was, therefore, rescinded as the headache had changed sides. She now fulfilled the diagnostic criteria for chronic migraine without aura. Candesartan was tried and not tolerated. Botulinum toxin injections administered according to the PREEMPT protocol had no effect. Her headache continued to increase in intensity despite her restarting her acupuncture sessions. Her repeat MRI surveillance study showed an increase of 3 mm in an otherwise previously stable pituitary macroadenoma.

Four years and 10 months after her initial presentation, she developed a new diplopia. Examination showed a left cranial nerve (CN) VI palsy, with sensory loss in CN V₁, V₂ and V₃. The clinical signs were consistent with a left cavernous sinus syndrome. Subsequent CT study of her head, intracranial CT venogram, and contrast-enhanced MRI showed enhancing abnormal tissue in the left cavernous sinus. She went on to receive a lumbar puncture which showed positive oligoclonal bands in cerebrospinal fluid only. The clinical picture was now consistent with Tolosa-Hunt syndrome and she was started on steroids.

Since her referral to the pituitary multidisciplinary team earlier on in her disease course, she continued to receive follow-up from neurosurgery and endocrinology. She did not develop any pituitary or vision related complications despite her ongoing headaches. The possibility of infiltrative disease was considered but it was decided that this was unlikely based on her imaging findings. Other causes of her headache were considered, such as an incidental right maxillary sinus thickening on her MRI study. She was referred to the otolaryngology team where she was reassured. She was also referred to the sleep team, where she received a diagnosis of obstructive sleep apnoea. She did not tolerate continuous positive airway pressure therapy.

Investigations

Her initial presentation was consistent with a primary headache syndrome. Therefore, the relevant diagnostic criteria were applied and investigations were performed on a screening basis. She had a normal CT study of her head at the time of presentation and an enlarged pituitary on subsequent MRI study of her head. The latter is a common finding and was not felt to be relevant at the time, although it led to serial imaging surveillance. With the benefit of hindsight, it is currently felt that her pain-free period of approximately half a year during her disease course was correlated with a slight volume reduction of the pituitary enlargement.

When she developed diplopia, her neurological examination was consistent with a left-sided cavernous sinus syndrome. She was investigated acutely with a CT study of her head and an intracranial CT venogram to look for a comorbid venous sinus thrombosis. This was excluded but there was a slight fullness noted in the posterior aspect of the left cavernous region. Dedicated MRI with contrast subsequently confirmed enhancing abnormal tissue in the left cavernous sinus. Sequential coronal T1 postcontrast MRI sequences are shown in figure 1.

Figure 1.

Sequential coronal T1 postcontrast imaging, with symptom onset on month 1. (A) Initial scan performed on month 6 demonstrates a ‘full’ pituitary which reduces in volume by month 47 (E), correlating with a slight improvement with patient symptoms. (H) In the dedicated scan performed in response to her new signs (month 59A), the pituitary volume has again increased with loss of the normal superior concavity to the gland. There is also gross asymmetric left cavernous sinus enlargement and pathological enhancement. Both of these findings completely resolve with steroid therapy with normal appearances on subsequent follow-up scan performed in month 66 (I) with no appreciable difference despite worsening symptoms in month 73 (J).

Laboratory analysis of her serum (table 1) had been unremarkable except for a slightly raised erythrocyte sedimentation rate (ESR) of 32, which was within normal limits for her age. When she developed new signs, further serological testing returned a positive atypical p-antineutrophil cytoplasmic antibody (p-ANCA) pattern of uncertain significance. She received a lumbar puncture which showed a normal protein, glucose, ACE, and positive cerebrospinal fluid oligoclonal bands (table 1). She was further screened for a malignant process with a CT study of her chest abdomen and pelvis which showed evidence of endometrial thickening, later confirmed to be a fibroid, and thus felt to be incidental to the clinical picture.

Table 1.

Laboratory analysis of serum and cerebrospinal fluid.

Serum
FBC	Mild thrombocytosis, otherwise normal
UE	Normal
LFT	Normal
CRP	Normal
ESR	Between 25 and 34 over 3 years
HIV	Antigen/antibody negative
Hepatitis B	Surface antigen negative
Hepatitis C	Antibody negative
Borrelia serology	IgM and IgG negative
TFT	Normal
B12	Normal
Folate	Normal
Serum electrophoresis	Normal
ANA	Negative
ANCA	Atypical p-ANCA pattern
TB Quantiferon	Indeterminate
Cerebrospinal fluid
Opening pressure	Lumbar puncture completed in sitting position due to difficulty
Glucose	3.3 mmol/L
Paired serum glucose	5.2 mmol/L
Protein	0.30 g/L
Albumin	202
ACE	<20
Oligoclonal bands (OCB)	Oligoclonal
Paired serum OCB	Normal
Cytology	Acellular
Microscopy	White cell count 0, red blood cells 0
PCR	Negative for adenovirus, HSV, VZV, enterovirus, parechovirus

ANA, antinuclear antibody; ANCA, antineutrophil cytoplasmic antibody; CRP, C reactive protein; ESR, erythrocyte sedimentation rate; FBC, full blood count; HIV, human immunodeficiency virus; HSV, herpes simplex virus; LFT, liver function tests; OCB, oligoclonal bands; TB, tuberculosis; TFT, thyroid function tests; UE, urea and electrolytes; VZV, varicella zoster virus.

The pituitary multidisciplinary team considered a biopsy of the affected area of the brain, but this was considered too risky given the location of the enhancing tissue.

Differential diagnosis

Her initial presentation with a 3-month long history of headache of moderate intensity, a stabbing (interpreted as pulsating) quality, associated with no neurological signs and a normal CT study of her head, was best explained by a probable chronic migraine without aura, as she had a history of pregnancy-related migraines, no other medical history, and was otherwise systemically well. It was felt that her headache symptoms favoured a diagnosis of probable chronic migraine without aura over chronic tension-type headache, as the headaches were unilateral, and a tightening quality was not described. The population prevalence of chronic migraine is 2%, rising to 8% in patients suffering from episodic migraine.³

When she developed lacrimation in the affected side, interpreted as autonomic symptoms, it was decided to try indomethacin, the response to which forms part of the diagnostic criteria for hemicrania continua.² This diagnosis was rescinded when her headache changed sides, a phenomenon observed in chronic migraine without aura.³ By then, she had developed nausea with her headache, fulfilling the diagnostic criteria for chronic migraine without aura.

However, the development of a persistent left cavernous sinus syndrome refutes this original diagnosis, as signs associated with migraine tend to be transient.³ Despite the diagnostic criteria for Tolosa-Hunt Syndrome requiring clinical signs to appear less than 2 weeks after the onset of the headache,² it was the best diagnosis to account for her clinical picture. Recurrent painful ophthalmoplegic neuropathy was considered but she had MRI evidence of parasellar pathology.²

Secondary causes of her headache were considered given her atypical p-antineutrophil cytoplasmic antibodies, mildly raised and cerebrospinal fluid oligoclonal bands. Common infective causes were felt unlikely with a negative cerebrospinal fluid culture and a cerebrospinal fluid white cell count of 0. Atypical infective causes such as tuberculosis and neuroborreliosis were also unlikely given the patient demographics and time-course of symptoms. Her Borrelia IgM and IgG were negative. Other inflammatory causes such as lymphoma and sarcoidosis were also considered but again the time-course of her symptoms is inconsistent with this. Her symptoms were inconsistent with multiple sclerosis and her brain parenchyma was normal on serial MRI studies. IgG4 disease was considered after treatment had started and felt to be unlikely as her post-treatment serum immunoglobulin subclasses were normal. The authors note that cerebrospinal fluid oligoclonal bands have previously been reported with Tolosa-Hunt syndrome.⁴

Atypical p-ANCA antibodies are associated with drug induced vasculitis and have also been reported in association with eosinophilic granulomatosis with polyangiitis.⁵ This was felt to be unlikely as her eosinophil count has never risen above 10% of her white cell count and she did not display evidence of systemic illness (asthma, sinus disease, peripheral neuropathy or rash) throughout her disease course.

Treatment

She was treated with a 3-day course of intravenous methylprednisolone followed by maintenance prednisolone 60 mg once a day. Following this, she reported a marked improvement in her headaches and diplopia the next day. After 2 weeks on 60 mg once a day, her prednisolone dose was reduced by 5 mg every 2 weeks to a maintenance dose of 20 mg once a day. It was further reduced by 1 mg every 2 weeks until 10 mg once a day.

Outcome and follow-up

After her course of intravenous methylprednisolone, her symptoms completely resolved. This correlated with MRI studies showing resolution of the presumed inflammatory changes in the cavernous sinus and improvement in appearances of the pituitary gland, with an overall volume reduction of the gland. This implied a causal link between these observed inflammatory changes and her symptoms.

However, 8 months later, her headache returned as she was tapering down her steroids. She had only managed to remain symptom free for a short period on prednisolone 10 mg once a day before the relapse of her headache. Her prednisolone dose was therefore increased to 30 mg once a day. She was reinvestigated with a MRI study of her pituitary gland and cavernous sinus which showed stable appearances of the pituitary. There was no change in volume and morphology and no recurrence of the enhancing abnormal tissue in the left cavernous sinus. It is postulated that her symptoms are due to ongoing microscopic disease.

The increased dose of steroids did not offer her complete relief of her symptoms and she still suffered from episodic exacerbations in the morning. She also noticed steroid-associated side effects of fluid retention and weight gain. It was suggested that prednisolone 30 mg once a day be continued for a further month before reducing it by 5 mg every month to a maintenance dose of 20 mg once a day, before further reducing it by 1 mg every month. Azathioprine was started as a steroid sparing agent and her dose was slowly increased to 175 mg once a day. Five months later, her pain control remained suboptimal. Therefore, she was again treated with a 3-day course of intravenous methylprednisolone which again resulted in complete symptom resolution.

Discussion

To the authors’ knowledge, this is the only case of a Tolosa-Hunt syndrome with a headache phenotype resembling hemicrania continua. Her ipsilateral lacrimation, which was used to aid this diagnosis, was in hindsight felt to be secondary to local irritation causing activation of the trigeminal-parasympathetic pathway. It should be noted that she never developed a CN VII palsy. She did not have clinical signs in the beginning, hence the diagnosis of Tolosa-Hunt syndrome was not considered. Her cavernous sinus syndrome manifested 4 years later on the opposite side. In hindsight, this was the most likely cause of her right-sided headache. The possibility of more than one headache type was considered but felt to be unlikely, given the resolution of her symptoms and imaging findings with steroid therapy.

The authors believe this is the only case of Tolosa-Hunt Syndrome where serial imaging showed pituitary enlargement with no evidence of pituitary failure, causing the misdiagnosis of an incidental pituitary macroadenoma unrelated to her chronic headaches. Pituitary involvement with Tolosa-Hunt syndrome has previously been reported, and these cases fulfilled the diagnostic criteria of Tolosa-Hunt syndrome from presentation,^6–9 in contrast with this case.

In this case, the spontaneous resolution of her right-sided headache correlated with a concurrent spontaneous reduction in size of the pituitary on her surveillance scans. Pituitary size reduction has previously been reported alongside a case of treated Tolosa-Hunt syndrome.¹⁰

The subsequent involvement of the left side fits with a relapsing-remitting course, consistent with the diagnosis of Tolosa-Hunt Syndrome. The timely resolution of symptoms alongside improvement in scan findings after starting steroid treatment further supports Tolosa-Hunt Syndrome as the unifying diagnosis for her 4-year history of symptoms. The authors could not obtain a histological diagnosis but it is recognised that biopsy is risky and should be reserved for particularly difficult cases.¹ The authors recognise that the diagnostic criteria for Tolosa-Hunt Syndrome defines the headache as preceding the cranial neuropathies by less than or equal to 2 weeks,² but cannot find another diagnosis that better accounts for her symptoms.

The authors may have achieved her diagnosis earlier had they obtained dedicated cavernous sinus imaging from the start. Retrospective assessment of the pituitary magnetic resonance images did not suggest a right-sided abnormality to correlate with her initial right-sided symptoms. However, a limitation here is that standard T1 imaging precontrast and postcontrast is the mainstay for pituitary assessment. When reviewing the cavernous sinus and orbits, fat saturating imaging is imperative. A fat saturated T1 contrast study may have revealed subtle asymmetric enhancement.

By the time of diagnosis, the cavernous asymmetry with a left bulk was readily appreciable in the pituitary T1 imaging and is well depicted in figure 1. Reviewing her blood results over the years, the only abnormality was a persistently elevated ESR which was within normal limits for age.

Some have previously argued that the Tolosa-Hunt Syndrome eponym is outdated, as it remains a diagnosis of exclusion, where multiple pathological entities can produce the same set of symptoms.¹¹ With this case, the authors argue that the syndrome itself may need redefinition, as symptoms may not stay on the same side, nor are cranial neuropathies certain.

Patient’s perspective.

I have had headaches for over 6 years now. The pain started on the right hand-side which affected my ability to work or drive. My right eye semi-closed with the pain. The pain moved to the left and became much worse. The pain was down the left hand-side of my head like nerve pain and through my face and behind my left eye. My eye would not move across to the left and so gave me double vision. I could not drive or work. I was unable to use the computer. For over 3 months, I was unable to lie down on a pillow and slept sitting up, propped up by pillows; any contact with the head touching anything was unbearable. Taking the steroids 1 g intravenously stopped the headaches by day two. I have had a relapse with the pain and had to go back onto pain killers. I am now taking, 14 mg Prednisolone steroids daily, 175 mg Azathioprine and Gabapentin to control the headaches. I had another dose of the steroids intravenously; three doses of 1 g per day of Prednisolone.

Learning points.

• Tolosa-Hunt syndrome can change sides.

• Cranial nerve palsies can present late in Tolosa-Hunt syndrome.

• Maintain a high index of suspicion where ‘incidental’ findings are found on imaging, especially in patients who remain symptomatic.

• Consider dedicated T1 fat saturated cavernous sinus imaging in patients presenting with trigeminal autonomic cephalalgias-like syndromes and pituitary enlargement, even if cranial neuropathies are absent.

Ethics statements

Patient consent for publication

Consent obtained directly from patient(s).