Brief Report

Reversible cerebral vasoconstriction syndrome following indomethacin

Cephalalgia 2014, Vol. 34(14) 1181–1186 ! International Headache Society 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0333102414530526 cep.sagepub.com

Zeljka Calic1,2, Ho Choong1,2, Glen Schlaphoff3 and Cecilia Cappelen-Smith1,2 Abstract Background: Reversible cerebral vasoconstriction syndrome (RCVS) is characterized by severe thunderclap headaches and transient segmental cerebral arterial vasoconstriction. Precipitating factors, including the postpartum state and exposure to vasoactive substances are identified in approximately 50% of cases. Non-steroidal anti-inflammatory drugs have rarely been associated with RCVS. Case description: We report a case of a 51-year-old female with RCVS after administration of indomethacin given to relieve pain caused by renal colic. Cerebral imaging showed non-aneurysmal cortical subarachnoid hemorrhage, and formal angiography demonstrated widespread multifocal segmental narrowing of medium-sized cerebral arteries. These changes resolved on repeat angiography at 3 weeks. Discussion: Indomethacin is a commonly used drug for treatment of certain primary headache disorders. To date, its mechanism of action remains unclear. A well described side effect of indomethacin is headache, which may be secondary to its vasoconstrictive effects. In our case, we postulate indomethacin, either alone or in combination with emotional stress from pain, triggered or exacerbated an underlying predisposition to RCVS. Keywords Thunderclap headache, indomethacin, reversible cerebral vasoconstriction syndrome Date received: 18 September 2013; revised: 15 November 2013; 7 January 2014; accepted: 28 January 2014

Introduction Reversible cerebral vasoconstriction syndrome (RCVS) is an increasingly recognized syndrome characterized by severe thunderclap headaches (TCH) with or without other neurological symptoms, and diffuse segmental vasoconstriction of cerebral arteries that resolves spontaneously within 3 months (1). It is more common in females, who typically present in the fifth decade, and are, on average, a decade older than male patients with RCVS (2). Although, the majority of patients with RCVS recover completely, 10% of patients may experience permanent neurological disability (3). Complications of RCVS include localized cortical subarachnoid hemorrhage (cSAH), ischemic stroke, intraparenchymal hemorrhage, and posterior reversible encephalopathy syndrome (2–4). Cerebral infarcts are typically located in ‘watershed’ regions and mainly occur during the second week (4). RCVS has been described in many clinical contexts and after use of various medications and drugs (2).

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used to treat headache, and are the first-line treatment for migraine. NSAIDs are not generally associated with the RCVS. Indomethacin is an NSAID with specific effectiveness in a variety of primary headache disorders including paroxysmal hemicrania and hemicrania continua (5). Headache is also a known side effect of indomethacin. It has been reported to cause RCVS in a single previous case report (6). Here, we report a case of RCVS after indomethacin was given 1 Department of Neurology and Neurophysiology, Liverpool Hospital, Australia 2 South Western Sydney Clinical School, University of New South Wales, Australia 3 Department of Radiology, Liverpool Hospital, Australia

Corresponding author: Cecilia Cappelen-Smith, Department of Neurophysiology, Liverpool Hospital, Locked bag 7103, Liverpool BC, NSW 1871, Australia. Email: [email protected]

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for acute pain and demonstrate formal angiographic changes and the resolution of these changes on repeat angiography at 3 weeks. This case occurred in the context of acute pain, the emotional stress of which may have compounded a trigger effect of the indomethacin. In addition, triptans given later in the patient’s presentation may have exacerbated an existing RCVS.

Case report A 51-year-old female presented to the Emergency Department with subacute onset of severe left renal angle pain. She had been previously well, took no regular medications, was a non-smoker and had no personal history of migraine or non-migraine headaches. There was no family history of migraine. Non-contrast CT scan of the abdomen was normal. The provisional diagnosis was renal colic and analgesia with oxycodone (5 mg) and paracetamol (1 g) was given with moderate resolution of pain. Indomethacin (100 mg, as a suppository) was given 6 hours after the initial analgesia, with complete relief of renal angle pain, and she was discharged home. After discharge and 1 hour after indomethacin was given, she developed a severe abrupt onset TCH in association with vomiting. The headache was relieved with self-administered tramadol. She did not return to the hospital. For the next 24 hours she was headache-free. She then woke from sleep in the early hours of the following morning (day 3) with another TCH and vomiting. She consulted her family doctor (day 3) and was prescribed rizatriptan wafers (10 mg), of which she took three over the next 24 hours, for recurrent severe headaches with minimal improvement. Neurological examination was normal. A CT brain and CT angiogram (day 4) organized by the family doctor showed parafalcine cSAH (Figure 1), no aneurysm and widespread multifocal narrowing of cerebral arteries. She was then referred and admitted to hospital (day 4). Lumbar puncture was not performed as she did not return to hospital until day 4 after the initial TCH, and by then imaging had confirmed non-aneurysmal cSAH and multifocal narrowing of cerebral arteries. Routine blood tests, urinalysis, vasculitic screen, and HIV, hepatitis B and C testing were unremarkable. Transesophageal echo was normal. CT mesenteric, splenic and renal angiography was normal. MRI brain (day 7) confirmed subarachnoid hemorrhage, but was otherwise normal. Formal digital subtraction angiography (DSA) on day 7 after the initial TCH showed widespread multifocal narrowing of medium-sized cerebral arteries and no aneurysm was seen (Figure 2(a)). There was beading in both internal carotid arteries consistent with fibromuscular dysplasia.

Figure 1. CT brain demonstrates parafalcine cortical subarachnoid hemorrhage. (a) Axial view, (b) coronal view.

She was commenced on verapamil 90 mg daily from admission (day 4), which was later increased to 90 mg bd (day 12). She had further TCHs on days 7 and 9 after initial onset. These were relieved with oxycodone and paracetamol. She had low-grade intermittent headaches until day 24. Repeat formal DSA on day 24 showed resolution of vessel narrowing (Figure 2(b)). The beading in both internal carotids persisted, consistent with fibromuscular dysplasia. She was discharged on day 25 after initial TCH onset. Figure 3 depicts a timeline summary of headache severity, investigations and treatment commenced during admission until discharge on day 25. She was continued on verapamil 90 mg bd. At review at 2 months, she was well, headache-free and had returned to full-time work as a librarian.

Discussion Headache caused by RCVS is characterized by TCH recurring over 1-2 weeks, often triggered by exertion,

Calic et al.

Figure 2. (a) Formal digital subtraction angiography (DSA) of left internal carotid artery (ICA) on day 7 demonstrates areas of multifocal narrowing of medium-sized cerebral arteries. (b) Formal DSA of left ICA on day 24 shows resolution of constricted arteries.

Valsalva, emotion or sexual activity (7). The recently published International Classification of Headache Disorders, 3rd edition (ICHD-III) diagnostic criteria for headache attributed to RCVS are summarized in Table 1. TCH is a severe high-intensity headache of abrupt onset, with pain reaching a maximum intensity in less than 60 seconds (7–9). A TCH may last from 5 minutes to several days. It may be single or recurrent. TCH requires urgent investigation. This should include a non-contrast CT brain to exclude intracerebral hematoma and tumors, followed by a lumbar puncture, if CT is non-diagnostic, to exclude aneurysmal subarachnoid hemorrhage. Vascular imaging and

1183 MRI brain should be performed if CT and lumbar puncture are normal, to exclude arterial dissection, venous sinus thrombosis, pituitary apoplexy, spontaneous intracranial hypotension and RCVS (1,2). RCVS is characterized by severe recurrent TCHs (8) with or without other acute neurological symptoms and signs or seizures (3,7). CT brain in RCVS may reveal cSAH in 20-34% (2) over the convexities of the cerebral hemispheres (3,10). CSF is normal or near normal. The gold standard for diagnosis in RCVS is angiography which is abnormal with multifocal segmental vasoconstriction of cerebral arteries (3). Imaging may also reveal ischemic stroke, intracerebral hemorrhage and edema consistent with posterior reversible encephalopathy syndrome. MRI, CT and angiography can be normal in the first week (10,11). Our patient’s initial TCH occurred shortly after discharge from hospital after treatment for acute renal colic. She remained at home until day 4 despite recurrent TCHs, and by then an outpatient CT scan had detected cSAH and multifocal segmental narrowing of cerebral arteries. She was then re-admitted to hospital. A lumbar puncture was not performed as imaging results confirmed the diagnosis. Vasospasm secondary to the patient’s relatively small cSAH was considered unlikely to account for the diffuse vascular changes seen on angiogram. A disproportionate degree of vasospasm versus size and location of cSAH is a recognized finding in RCVS (2). Although RCVS may occur spontaneously, at least half the cases are secondary, mainly occurring post partum and/or following vasoactive drug use, either illicit drugs or sympathomimetic agents (2,12–14). Certain underlying conditions including fibromuscular dysplasia may also predispose to RCVS (13). The pathophysiology of RCVS remains unknown, but is believed to involve a transient disturbance in control of cerebrovascular tone causing segmental arterial vasodilatation and vasoconstriction (10). Hypothetical mechanisms involve endothelial dysfunction and sympathetic deregulation (13). The temporal clinical course and angiographic findings suggest segmental involvement of vascular beds. Initial involvement of small distal arteries progresses over days to weeks to involve medium- and large-sized arteries (10). Recently, changes in a brain-derived neurotrophic factor (BDNF) have been associated with disorders that affect vascular tone. Reports suggest carriers of the valine allele of the BDNF gene polymorphism may have an increased risk of developing severe vasoconstriction and complications associated with RCVS (15). NSAIDs are widely used analgesics for the treatment of headache. The various NSAIDs exhibit different clinical profiles. Indomethacin and the other NSAIDs share mechanisms of action including cyclooxygenase

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Indomethacin given

Severe headache (TCH) Moderate headache

Verapamil started

Mild headache

Verapamil dose increased

No headache

0

1

2

3

4

5

6

7

8

9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 Days

Figure 3. Profiles of headaches, investigations and treatment given day 1 to day 25 (¨ severe headache,  moderate headache, # mild headache,  no headache). Day 1: First Thunderclap headache (TCH) 1 hour after indomethacin, resolved with self-administered tramadol. Day 3: TCH, Family doctor prescribed rizatriptan. Day 4: Ongoing TCH, no response to rizatriptan, outpatient CT brain/ angio showed cortical subarachnoid hemorrhage (cSAH), and multifocal narrowing of cerebral arteries, no aneurysm; hospitalized; verapamil 90 mg daily started. Day 7: TCH, digital subtraction angiography (DSA) confirmed CT angio findings, MRI brain cSAH. Day 9: TCH, CT brain no change. Day 12: Verapamil increased to 90 mg bd. Day 24: DSA showed resolution of vessel narrowing. Day 25: Discharged home. Day 4-25: Regular paracetamol and intermittent oxycodone given.

Table 1. Diagnostic criteria for headache attributed to reversible cerebral vasoconstriction syndrome (RCVS). A. Any new headache satisfying criterion C B. RCVS has been diagnosed C. Causation linked with at least one of the following: 1. headache, with or without focal deficits and/or seizures, and angiographic findings diagnostic of RCVS 2. headache has either or both of these features: a) thunderclap onset, and recurrent during first month b) triggered by sexual activity, exertion, Valsalva, emotion, and/or bathing 3. no new significant headache 1 month after onset D. No other more appropriate ICHD-3 diagnosis, and aneurysmal subarachnoid hemorrhage excluded Source: Adapted with permission from Cephalalgia 2013; 33: 629–808 (ref. 7).

inhibition. Other mechanisms of action remain unknown. Indomethacin is first-line recommended therapy for a range of primary headache disorders including paroxysmal hemicrania and hemicrania continua (16). Paradoxically, headache induced by indomethacin is a known side effect reported in numerous, mainly earlier publications (17). Headache was found to be more common in those on a higher versus lower dose of indomethacin (5). The mechanisms of headache causation by indomethacin remain unknown. Medication overuse

is one postulated mechanism. Aseptic meningitis is a rare but reported cause of headache with NSAID use (5). NSAIDs are not generally associated with RCVS. There is only one prior case report in the literature of RCVS after administration of indomethacin (6). The patient in this report had severe headache onset 30 minutes after a single 50 mg intravenous dose of indomethacin for treatment of migraine headache and the diagnosis was supported by reversible changes on transcranial Doppler (6). Our cases are similar in that headache onset occurred within 1 hour of indomethacin administration and both showed reversible vascular changes. However, the other case occurred in a patient with an established history of migraines and resolved within 16 hours. Our patient had no prior history of migraine headaches and had a more typical clinical and angiographic course for RCVS. In human studies, indomethacin has been shown to reduce basal and CO2 stimulated cerebral blood flow in healthy control subjects and in raised intracranial pressure presumably by producing cerebral vasoconstriction (18). The mechanism by which indomethacin exerts its effect on cerebral vessels is not well understood. However, the action is partly mediated by inhibition of prostacyclin formation, a potent endogenous vasodilator (19). Other experimental evidence suggests that indomethacin causes vasoconstriction by inhibiting nitric oxide-induced vasodilation (16). This effect

Calic et al. occurs uniquely with indomethacin and not with other NSAIDs (16). This may account for the different clinical profile of indomethacin in the treatment of headache. In our patient, a non-migraneur, the close relationship between administration of indomethacin, onset of TCH and angiographic confirmation of reversible multifocal vasoconstriction in medium-sized vessel branches suggests a vasoconstrictive effect at least in part triggered by indomethacin. Other factors may have contributed to her presentation. Emotional distress is a recognized trigger for RCVS as described in the ICHD-III criteria. Our patient originally presented with severe acute renal colic pain and the emotional distress caused by this pain may have resulted in sympathetic activation and contributed to the onset of the RCVS. She also had intercurrent fibromuscular dysplasia, which is an independent risk factor for RCVS (13). Indomethacin may therefore have triggered RCVS in the context of a predisposing condition and acute emotional distress. The patient’s subsequent triptan use may have aggravated or exacerbated the established RCVS. Triptans can precipitate RCVS (20) and exacerbate an existing RCVS (21,22). Triptans may also alleviate

1185 headache intensity in undiagnosed subarachnoid hemorrhage and result in misdiagnosis and a delay in appropriate management (22). Therefore, triptans should never be prescribed as treatment for an acute unusual headache. Oxycodone was also administered to our patient in the initial stages of her presentation for acute renal angle pain and given later as analgesia for ongoing headaches. Although oxycodone has been listed as an intercurrent medication in at least one prior case report of a patient with RCVS (23), no direct correlation has been published to establish oxycodone as a distinct trigger for RCVS. Her subsequent headaches were managed during the hospital admission with paracetamol and oxycodone with relief of recurrent symptoms. Paracetamol has not been described as a trigger for RCVS. We postulate that the use of indomethacin either alone or in combination with emotional distress and vasoactive agents including triptans may trigger or exacerbate an underlying predisposition to RCVS. Caution should be used when prescribing triptans and they should not be given for acute new onset unusual headaches until other causes including subarachnoid hemorrhage and the RCVS have been excluded.

Clinical implications . Physicians should be aware of this potential but rare complication in patients presenting with thunderclap headache following the administration of indomethacin. . Indomethacin should be used with caution in patients with an underlying predisposition to RCVS. Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflict of interest None declared.

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