Long-term Ergotamine Derivative Therapy for Migraine Associated with Pachymeningitis and Sixth Cranial Nerve Palsy

ABSTRACT

Chronic use of ergotamine derivatives has been well described in the literature to cause retroperitoneal, pleural, pericardial and valvular fibrosis. While acute migraine treatment advances have resulted in a reduction of ergotamine derivatives prescribing, they are still considered appropriate for some patients. We report a case of diffuse pachymeningitis with symptomatic right sixth cranial nerve palsy who had a history of long-term Cafergot© suppository use. To the best of our knowledge, this is the first case to temporally associate ergotamine derivatives with pachymeningitis.

Introduction

Pachymeningitis is a rare condition of diffuse or localised fibrous thickening of the dura mater. Described aetiologies include infection, autoimmune diseases, neurosarcoidosis, CNS lymphoma and after exclusion of these causes; idiopathic.¹ Clinical manifestations of pachymeningitis include headaches, cranial nerve palsies and myelopathy.¹ In the literature, only two case reports have described drug-associated pachymeningitis; these included non-steroidal anti-inflammatory drugs and adalimumab for rheumatoid arthritis.^2,3 In these case reports, the fibrotic processes resolved after ceasing the medication.^2,3

Ergotamine has been used for the acute treatment of migraine since 1926 and has a relatively low-receptor selectivity for adrenergic serotonergic and dopamine receptors and consequently has a multitude of described adverse drug reactions.⁴ Chronic ergotamine use has been associated with fibrotic processes in the retroperitoneum, pleura, pericardium and heart valves.⁵ No literature has been published associating ergotamine use with dura fibrosis.

Case report

A 57-year-old man presented with a four-day history of horizontal diplopia worse on right lateral gaze and headaches. He described migraines since a teenager and increasing frequency of headaches in the 2 years preceding this presentation that were worse in the morning and when lying down. He had a significant medical history of long-standing reduced visual acuity in his left eye to 6/12 due to congenital toxoplasmosis infection; however, this is was unchanged from previous ophthalmology records. The patient was initially started on Cafergot S 2/100 mg (ergotamine tartrate/caffeine) suppositories 10 years prior and would use 2–3 per month for acute migraines. He changed pharmacist to a compounding pharmacist where he was able to obtain bulk supply of Cafergot suppositories at a significantly cheaper price. Subsequently, he increased his use of ergotamine suppositories to 3 per week in the 3 months prior to his presentation.

At the initial presentation, ophthalmic examination elicited a right sixth nerve palsy with inability to abduct his right eye past the midline. Other extraocular movements were normal. No visual field defect was detected. His pupils were equal and reactive to light, with no relative afferent pupillary defect. Funduscopic examination was normal. No other cranial nerve abnormality was detected. Upper and lower limb neurological examination did not elicit any weakness, incoordination or sensory disturbance. The patient did not express any symptoms or show signs of respiratory system disease, otitis media, mastoiditis or sinusitis.

His brain magnetic resonance imaging, shown in Figure 1, was reported as consistent with pachymeningitis with diffuse pachymeningeal enhancement and thickening (Figure 1a, b, c), with no flattening of the pons or slumping of the midbrain or tonsillar herniation to suggest intracranial hypotension as an underlying cause (Figure 1d). The only view visualising cranial nerve VI was at the skull base however, which does not show increased pachymeningeal enhancement at this region (Figure 1e). His blood tests, autoimmune and neuropathy screen revealed normal full blood count, electrolytes, erythrocyte sedimentation rate, C-reactive protein, anti-nuclear antibodies, anti-neutrophilic cytoplasmic antibodies, antiphospholipid screen, hepatitis B, hepatitis C, lymphocyte surface markers and immunoglobulin G levels. A lumbar puncture was performed with an opening pressure of 11 cm H₂O and revealed a mildly elevated cerebrospinal fluid (CSF) protein 0.56 g/L (0.15–0.45) and normal glucose with no cells or growth on culture. Flow cytometry of the CSF showed 62% of total cells were lymphoid gated but did not reveal any abnormal clonal population and cytology was negative for malignancy. Computerised tomography of the chest, abdomen and pelvis was performed looking for lymphoma with nil lymphadenopathy seen. Hence, a diagnosis of idiopathic pachymeningitis was made.

Figure 1.

MRI scan.

(a) Axial eTHRIVE post-gadolinium showing diffuse pachymeningeal thickening and enhancement over bilateral cerebral convexities, (b) axial T2 FLAIR showing diffuse thickening of pachymeninges, (c) axial T1 SPIR post gadolinium showing diffuse thickening of pachymeninges, (d) sagittal T1 hypointensity of meninges pre contrast and no slumping of midbrain or tonsillar herniation and (e) axial T2 3D-DRIVE sequence of base of skull view of cranial nerve VI.

A neurosurgical decision regarding dural biopsy was sought but was considered to be futile for detecting neoplastic or other causes given the radiographically diffuse nature of the dural thickening. He was advised to cease the ergotamine derivative and was followed up in Neuro-Ophthalmology clinic. The patient experienced dramatic improvement of right eye abduction after cessation of the ergotamine derivative over a three month period, nicely illustrated by Figure 2. The photograph of Sydney harbour shows from shortly after his initial presentation in mid-November 2017 the diplopic images coming closer together, through to complete resolution by mid-January 2018. There was no administration of oral or intravenous steroids, or immune modulating agents such a azathioprine, cyclophosphamide or methotrexate, with the patient experiencing dramatic improvement after cessation of Cafergot© alone.

Figure 2.

Photograph of Sydney Harbour illustrating the functional improvement of the patient’s diplopia. The vertical lines demonstrate the two perceived images becoming closer together from mid-November 2017 to complete resolution by mid-January 2018.

Discussion

Ergotamine derivatives are hypothesised to be effective in migraine due to their specific serotonin 5-HT_2A receptor antagonist and 5-HT_1A receptor agonist effects that reduce serotonin-induced cerebral vasodilation.⁶ Silberstein published a review that estimated the incidence of a fibrotic side effect from methysergide, another ergotamine derivative medication, to be 1 in 5000 treated patients.⁷

The pathogenetic mechanism for ergotamine derivate induced fibrosis is hypothesised, albeit with limited evidence for retroperitoneal, pleural, pericardial and valvular disease, to be secondary to a rebound release of serotonin after bioelimination of ergotamine derivatives. This increased serotonin via feedback mediates myofibroblast proliferation with overproduction of collagen, fibronectin, tenascin and glycosaminoglycans.⁸ From our literature search, no published human studies were found exploring the effect of ergotamine on the dura mater. We postulate whether a similar rebound release of serotonin after ergotamine use could be the pathogenesis of pachymeningitis, similar to what is hypothesised to occur in other organs. The imaging could also suggest intracranial hypotension, but the patient did not have clinical features of this condition, namely a headache worse in upright posture but rather the contrary.

This case report highlights the importance of taking a thorough drug history in neuro-ophthalmic cases and serves as a reminder of the serious adverse effects associated with ergotamine derivatives.

Funding Statement

No funding was received.

Declaration of interest

The authors declare that there are no conflicts of interest. The authors alone are responsible for the writing and content of the article.

Patient consent

Informed patient consent was obtained prior to the publication of this case report.