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Home , Decongestant, Oxymetazoline, Xylometazoline

PRACTICE | CASES CPD

Recurrent thunderclap headaches from reversible cerebral syndrome associated with duloxetine, and medicamentosa

Hoang Pham MD, Stéphanie Gosselin-Lefebvre MD, Persia Pourshahnazari MD, Samuel Yip MD PhD n Cite as: CMAJ 2020 November 9;192:E1403-6. doi: 10.1503/cmaj.201234

52-year-old woman presented to the emergency depart- ment with 2 episodes of thunderclap headaches sepa- KEY POINTS rated by about 8 hours, both occurring during defeca- • Thunderclap headaches warrant emergent evaluation for tion.A She had a history of chronic , asthma, aneurysmal subarachnoid hemorrhage and reversible cerebral chronic back pain, and low mood without other major depressive vasoconstriction syndrome, which are the 2 most common features or suicidality. She had no history of . Her causes. consisted of a – , sal- • The most common cause of atraumatic convexal subarachnoid hemorrhage in patients aged 60 years or younger is reversible butamol taken as needed, duloxetine 60 mg/d (a serotonin- cerebral vasoconstriction syndrome. reuptake inhibitor [SNRI]) and xylometazoline • Exposure to vasoactive substances (e.g., topical nasal spray taken once daily. The patient and serotonergic medications) is a known risk factor for described periodic worsening of nasal congestion, which led her reversible cerebral vasoconstriction syndrome; multiple to increase her xylometazoline dosage. At the time of presenta- concomitant exposures may interact additively to further tion, she was using the nasal decongestant 2–3 times daily and increase the risk of reversible cerebral vasoconstriction she had been taking duloxetine daily for 1.5 years. She did not syndrome. have a history of tobacco smoking, problem drinking or recre- • All patients taking nasal should be counselled ational substance use. about the risk of if nasal decongestants are used regularly for more than 3–5 days and the risk of On examination, she was hypertensive at 215/108 mm Hg, but reversible cerebral vasoconstriction syndrome, especially if after receiving analgesia, and fluids, her pres- there are concomitant exposures to vasoactive substances. sure improved to 155/90 mm Hg. She had a Glasgow Coma Scale score of 15, a supple neck, and no associated focal neurologic deficits, activity or encephalopathy. She had severe into interhemispheric fissures, basal cisterns or ventricles. Com- in­ferior nasal turbinate hypertrophy; hyperemic nasal mucosa; puted tomography and CT angiography were adequate noninva- minimal thin, clear secretions; and moderate right nasal septal sive investigations in this case, because of the convexal pattern deviation without septal perforation. of the subarachnoid hemorrhage. We did not do a lumbar punc- Initial computed tomography (CT) of the head and CT angiog- ture, which is reserved for investigating thunderclap headache in raphy showed small areas of convexal subarachnoid hemorrhage the setting of a normal CT to exclude a small subarachnoid hem- as well as multifocal mild-to-moderate narrowing in the intra­ orrhage without an aneurysm seen on CT angiography.1 cranial arteries of the anterior and posterior circulation with a We tapered the duloxetine 60 mg/d down to 30 mg every string-of-beads appearance (Figure 1). The patient’s presenta- other day for 3 doses and stopped, after confirming that her pri- tion was compatible with reversible cerebral vasoconstriction mary indication was for sciatica, which was well controlled. We syndrome given the history of recurrent thunderclap headaches, also weaned and discontinued the xylometazoline, and given triggered by a Valsalva effect from straining, exposure to 2 vaso- the patient’s severe nasal congestion and comorbid asthma, we constrictive medications, and classic imaging findings of wide- prescribed montelukast 10 mg/d along with beclomethasone spread symmetric cerebral artery narrowing and small atrau- 50 µg, 2 sprays each nostril daily, as an effective and matic convexal subarachnoid hemorrhage. The term “convexal” safer long-term option for her nasal congestion related to sus- denotes a hemorrhage distribution limited to convexities of the pected . We discussed the rationale for using brain without involving adjacent brain parenchyma or extending intranasal steroids rather than decongestant sprays. Finally, to

© 2020 Joule Inc. or its licensors CMAJ | NOVEMBER 9, 2020 | VOLUME 192 | ISSUE 45 E1403 PRACTICE E1404 intracranial arterial stenoses in the bilateral anterior, middle arachnoid hemorrhageandmild intervalimprovementinthe angiographic stabilitybeforedischarge. Itshowedresolvedsub- After 2weeksoftherapy,we ordered repeatimagingtoverify release, a , 120 mg orally every 8 hours. the patientandstartedtreatment withverapamilimmediate hasten reversalofthecerebralvasoconstriction,weadmitted posterior circulation.Colloquially,thiscreatesa“string-of-beads”appearance (arrows).(A)Axial,(B,C)sagittaland(D)coronalviews. derclap headaches,showingmultifocalsegmentalmild-to-moderate stenosesbilaterallyinthecircleofWillisanditsbranchesbothanterior Figure 1:Computedtomographyangiogramoftheheadina52-year-oldwoman whopresentedtotheemergencydepartmentwith2episodesofthun- CMAJ | NOVEMBER 9,2020 | VOLUME 192 follow-up. possible. Shehashadnofurther episodesofheadacheaslast vasoactive drugssuchasdihydroergotamine andtriptans,if nasal decongestants,serotonergic antidepressantsandother up inthestrokepreventionclinic, andweadvisedhertoavoid ing verapamilextendedrelease 180mgtwicedailywithfollow- and posteriorcerebralarteries.Wedischargedthepatienttak - | ISSUE 45 PRACTICE E1405 1–9 RCVS Unknown 10–76 40–45 Mean 10:1 > male, 2 to Female with > 60% of cases identifiable risk factor thunderclap Recurrent of 4) (mean headache 1–3 h Short duration normal often More deficit neurologic Focal with (if associated stroke) Seizure convexal Atraumatic SAH Normal (30%–70%) Ischemia hemorrhage Lobar reversible Posterior encephalopathy signs (i.e.,syndrome of areas bilateral matter white subcortical in vasogenic cerebral posterior oftenhemispheres, but head, on CT apparent on MRI) seen better segmental Multifocal cerebral (string vasoconstriction and beads) within 3 mo Reversible Normal or mild and cells white elevated or protein < 5% with life- of form threatening RCVS < 15%–20% mild deficit in 5%–6% Recurrence 3.4 yr at • • • • • • • • • • • • • • • • • • • • • Aneurysmal SAH 3–25/100 000 40–60 50 Peak > male after Female (1.6) fifth decade Hypertension smoking Cigarette history/genetic Family Alcohol Sympathomimetic Single thunderclap headache Sentinel headache (10%–43%) duration Longer level of Altered consciousness neurologic Focal deficit Seizure SAH Perisylvian Perimesencephalic subarachnoid intraparenchymal subdural hemorrhage, hemorrhage, intraventricular hemorrhage Aneurysm erythrocytes Elevated 4) tube 1 to (from Positive xanthochromia opening Elevated pressure 8%–67% rate Mortality rate (median mortality 32% in the US) of persistent Rate 8%–20% dependence 10 yr 2.2% at • • • • • • • • • • • • • • • • • • • • • • • • ISSUE 45 ISSUE | Note: CT = computed tomography, MRI = magnetic resonance imaging, RCVS = imaging, RCVS resonance MRI = magnetic tomography, = computed CT Note: hemorrhage. SAH = subarachnoid syndrome, vasoconstriction cerebral reversible Box 1: Comparison of aneurysmal subarachnoid hemorrhage hemorrhage aneurysmal of subarachnoid 1: Comparison Box syndrome vasoconstriction cerebral and reversible Characteristic Epidemiology Incidence yr Age, Sex, female-to- male ratio features Clinical Risk factors Headache features Physical examination tests Imaging and other imaging Brain Vascular imaging Lumbar puncture Prognosis and Mortality morbidity Recurrence VOLUME 192 VOLUME | , - 4 Other reported 2 NOVEMBER 9, 2020 NOVEMBER | The top 3 vasoactive The top 3 vasoactive 2,3 CMAJ The most common multiple multiple common most The 3 Exposure to a single vasoactive sub- - vaso cerebral reversible Differentiating 2,3 3 - The authors found that thunderclap head 2 Other less common vasoactive substances included Other less common vasoactive substances included 2,3 After her hospital stay, our patient also saw an allergist, who allergist, also saw an patient stay, our her hospital After rhage is reversible cerebral vasoconstriction syndrome. rhage is reversible cerebral vasoconstriction constriction syndrome from aneurysmal subarachnoid hemor- constriction syndrome from aneurysmal neurosurgeon, on-call the consulted we and essential, is rhage convexal subarach- who concluded that, based on the patient’s multivessel narrowing, noid hemorrhage pattern and multifocal was the most reversible cerebral vasoconstriction syndrome related to a rup- likely diagnosis, not subarachnoid hemorrhage most the younger, or years 60 aged patients In aneurysm. tured hemor subarachnoid convexal atraumatic of cause common used specific immunoglobulin E testing to identify an to an allergy to E testing to identify immunoglobulin used specific to her could be attributed her year-round congestion cats. Thus, avoid that she completely we recommended pet cat. Although for subcuta­ ready and opted her cat, she was not contact with an otolaryn- further assessed by She was neous . nonallergic factors contributing to severe gologist to identify consideration of nasal septal cor- with chronic nasal congestion, reduction. rection and turbinate stance was observed in 39%, and multiple exposures were docu- cases. of 14.5% in mented

Reversible cerebral vasoconstriction syndrome has a long list of list long a has syndrome vasoconstriction cerebral Reversible putative risk factors without a fully unifying mechanism; how- ever, drugs and conditions associated with vasoconstriction have been most consistently observed. Two prospective cohort stud- ies identified the postpartum state and exposure to at least 1 vasoactive substance as risk factors. Risk factors for reversible cerebral vasoconstriction syndrome The term thunderclap headache describes a headache that headache describes a headache that The term thunderclap at onset. The 2 most common and reaches maximal intensity - headache to consider are revers urgent causes of thunderclap and aneurysmal sub- ible cerebral vasoconstriction syndrome arachnoid hemorrhage (Box 1). A prospective study involving 173 syndrome patients with reversible cerebral vasoconstriction a history of migraines, found that 71% were female, 32% had and 8%–12% 49%–60% were exposed to vasoactive substances were postpartum. Reversible cerebral vasoconstriction syndrome versus vasoconstriction syndrome versus Reversible cerebral hemorrhage aneurysmal subarachnoid Discussion ache was present in 94% and tended to be recurrent (87%) and ache was present in 94% and tended to intercourse (27%), provoked (77%), and associated with sexual (19%). (22%) or acute emotional stress exertion substances were cannabis (20%–32%), selective serotonin reup- take inhibitors (SSRIs) (13%–21%) and nasal decongestants (13%). patches, ergots, triptans, SNRIs, epinephrine, cyclospo- rine and sulprostone. alcohol (binge drinking), cocaine, , interferon-α exposures involved cannabis with alcohol binge drinking (6%) or cannabis with a nasal decongestant (3%); an SSRI combined with associations include defecation, urination, cough, sneezing, cough, sneezing, associations include defecation, urination, showering. or bathing PRACTICE tion. to avoidhypotensioninthesettingofcerebralvasoconstric- according tocurrentstrokeguidelines,especiallybeingmindful strictly avoidingtriptans. High bloodpressure should betreated treatment of headache is recommended with simple , gestant spray,andsertraline,anSSRI. with chronicuseofoxymetazoline,anothertopicalnasaldecon- a 31-year-oldwomanwiththunderclapheadacheassociated syndrome. Similartoourcase,Loewenandcolleaguesdescribed was highlysuspiciousforreversiblecerebralvasoconstriction increased useofxylometazolineandchronicduloxetine new-onset recurrentthunderclapheadachesassociatedwith E1406 advise theirpatientsaccordingly. fessionals shouldbeawareof thesepotentialinteractionsand of reversiblecerebralvasoconstriction syndrome.Healthcarepro- sants, cannabisandalcohol(bingedrinking),mayincreasetherisk common vasoactivesubstances,suchasserotonergicantidepres - decongestants. Nasaldecongestantswhencombinedwithother negative impactsofreadilyaccessibleover-the-counternasal patients targetedandhighlyeffectivetreatments,discuss the symptoms, wecanexplorepossibleallergictriggerstoavoid,offer By conductingafullclinicalevaluationofchronicnasalobstructive caused byandtransientlyrelievedtheintranasaldecongestant. posing thepatienttoaviciouscycleofrefractorynasalcongestion tion, tachyphylaxisandimpairedmucociliaryclearance,predis - for morethan3–5days.Itcanmanifestasreboundnasalconges - (e.g.,,xylometazolineandphenylephrine) rhinitis duetoprolongeduseofatopicalα Rhinitis medicamentosaisaspecialtypeofmedication-induced severe chronicnasalcongestionandxylometazolineuse. patient wasalsodiagnosedwithrhinitismedicamentosabasedon Along withreversiblecerebralvasoconstrictionsyndrome,this cerebral vasoconstrictionsyndrome Rhinitis medicamentosaasariskfactorforreversible 4 weeksandangiographicresolutionby3months. tion syndromeisoftenself-limitedwithnonewsymptomsafter removal ofoffendingagents,asreversiblecerebralvasoconstric- drome. Themainstayoftreatmentisearlyrecognition,restand the managementofreversiblecerebralvasoconstrictionsyn- No randomizedcontrolledtrialshavebeenconductedtoguide syndrome Management ofreversiblecerebralvasoconstriction a nasaldecongestantwasobservedin1%ofcases. sodes ofthunderclapheadache. tolerated andarereasonable considerationsinrecurrentepi- receiving treatmentwithnimodipine,acalciumchannelblocker. and radiologicresolutionafterstoppingoxymetazoline spasm inaneurysmalsubarachnoidhemorrhage. striction syndrome,consistentwiththemanagementofvaso- gate cerebralvasoconstrictioninreversiblevasocon- blockers suchasnimodipine,verapamilandnicardipinetomiti- 10 Severalcaseseriessupporttheuseofcalciumchannel 6 5 CMAJ Thepatienthadclinical - | NOVEMBER 9,2020 6 6 Theyarewell 3 Symptomatic Ourpatient’s 5 | VOLUME 192 References

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5 1 8 2 4. 3. 6. 9. 7. . . . . Correspondence to:HoangPham,[email protected] lished andagreedtoactasguarantorsofthework. lectual content.Allauthorsapprovedthefinalversiontobepub- the manuscriptandallauthorsreviseditcriticallyforimportantintel- Contributors: HoangPhamandStéphanieGosselin-Lefebvredrafted General Hospital,UniversityofBritishColumbia,Vancouver,BC versity of British Columbia; Division of Neurology (Yip), Vancouver bec, Que.;DivisionofAllergyandImmunology(Pourshahnazari),Uni- sitaire de Québec–Hôpital de l’Enfant-Jésus, Université Laval, Qué Division ofNeurology(Gosselin-Lefebvre),Centrehospitalieruniver- ment ofMedicine,McGillUniversityHealthCentre,Montréal,Que.; Affiliations: DivisionofAllergyandImmunology(Pham),Depart- The authorshaveobtainedpatientconsent. This articlehasbeenpeerreviewed. Competing interests:Nonedeclared. necessity. Seeinformationforauthors atwww.cmaj.ca. encouraged. Consentfrompatients for publication of their storyis a ferential diagnosis,clinicalfeaturesordiagnosticapproach)are lows (1000wordsmaximum).Visualelements(e.g.,tablesofthedif- words maximum), and a discussionoftheunderlyingcondition fol- common problems.Articlesstartwithacasepresentation(500 important rareconditions,andunusualpresentationsof practical lessons.Preferenceisgiventocommonpresentationsof The sectionCasespresentsbriefcasereportsthatconveyclear, Macdonald de Boysson 2017; Kumar patients. Brain2007;130:3091-101. of reversiblecerebralvasoconstrictionsyndrome.Aprospectiveseries67 Ducros 2018; reversible cerebralvasoconstrictionsyndrome:acomparativestudy. Loewen 2010;​ hemorrhage: clinicalpresentation,imagingpatterns,andetiologies. and acuteinpatientstrokecare,update2018. mendations foracutestrokemanagement:prehospital,emergencydepartment, Lawton for reversiblecerebralvasoconstrictionsyndrome.Neurology2019;92:e639-47. Cappelen-Smith 2004; cerebral vasoconstrictionassociatedwithuseofoxymetazolinenasalspray. Boulanger 2012;43:1711-37. als fromtheAmericanHeartAssociation/AmericanStrokeAssociation. aneurysmal subarachnoidhemorrhage:aguidelineforhealthcareprofession- Anesthesia; Council onCardiovascularNursing; tion StrokeCouncil; Connolly Rocha syndrome: recognitionandtreatment.CurrTreatOptionsNeurol2017;19:21. 171: 389: 91: 74:893-9. EA, S, A, MT, AHS, e1468- 593- 655- ES Goddeau Boukobza Topcuoglu JM, RL, Vates Council onClinicalCardiology. Jr, H Hudon 4 | 66. ISSUE 45 , . Lindsay 78. Schweizer Rabinstein Parienti C GE. , RP ME, Calic M, Subarachnoid hemorrhage. Council onCardiovascularRadiologyandIntervention; MA, MP, Jr, Porcher Hill J-J, TA. Silva Z Selim Gubitz AA, , MD. Cordato Mawet Spontaneous subarachnoidhaemorrhage. Carhuapoma GS, Thunderclap headache and reversible segmental Thunderclap headacheandreversiblesegmental R, MH, G et al. et al. , et al. J et al. Council onCardiovascularSurgeryand D , . et al. The clinicalandradiologicalspectrum RCVS2 scoreanddiagnosticapproach Reversible cerebralvasoconstriction Canadian strokebestpracticerecom- Atraumatic convexalsubarachnoid Guidelines forthemanagementof JR, Int JStroke Primary angiitisoftheCNSand et al.; N EnglJMed American HeartAssocia- 2018; 13:​ 2017; 949- 377: 84. Neurology Neurology 257- Lancet Stroke CMAJ - 66.