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LETTERS TO THE EDITOR
Year : 2021  |  Volume : 24  |  Issue : 2  |  Page : 304-307
 

Ischemic stroke associated with chronic xylometazoline nasal spray misuse: A rare avoidable adverse event


1 Physician Doctor, Shree Krishna Hospital, Pramukhswami Medical College, Karamsad, Anand, Gujarat, India
2 Professor in Medicine Department, Shree Krishna Hospital, Pramukhswami Medical College, Karamsad, Anand, Gujarat, India
3 Sr. Consultant Neurologist, Professor and Head, Neurology, Shree Krishna Hospital, Pramukhswami Medical College, Karamsad, Anand, Gujarat, India

Date of Submission11-Apr-2020
Date of Acceptance03-May-2020
Date of Web Publication08-Jul-2020

Correspondence Address:
Soaham Desai
Sr. Consultant Neurologist, Professor and Head, Neurology, Shree Krishna Hospital, Pramukhswami Medical College, Karamsad, Anand, Gujarat - 388 325
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/aian.AIAN_291_20

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How to cite this article:
Patel J, Patel I, Desai D, Desai S. Ischemic stroke associated with chronic xylometazoline nasal spray misuse: A rare avoidable adverse event. Ann Indian Acad Neurol 2021;24:304-7

How to cite this URL:
Patel J, Patel I, Desai D, Desai S. Ischemic stroke associated with chronic xylometazoline nasal spray misuse: A rare avoidable adverse event. Ann Indian Acad Neurol [serial online] 2021 [cited 2021 Jun 19];24:304-7. Available from: https://www.annalsofian.org/text.asp?2021/24/2/304/289316




Sir,

A 54-year-old male presented with acute onset vertigo, with imbalance, with swaying towards the side with dysarthria, dysphonia, and dysphagia. On examination, he had decreased pain and temperature sensations in right upper and lower limbs, loss of pain, and temperature sensations on the left side of the face, truncal ataxia with swaying towards left, left-sided cerebellar signs and left Horner' syndrome. He did not have any conventional stroke risk factors like hypertension, diabetes mellitus, dyslipidemia, tobacco or alcohol use, or positive family history. His magnetic resonance imaging (MRI) of the brain was suggestive of acute left lateral medullary infarct with left vertebral artery stenosis [see [Figure 1] and [Figure 2]. His blood pressure at admission and through the course, hemogram, liver function test, renal function test, glucose, lipid profile, electrocardiogram, 2D echocardiogram, and neck vessel angiography were normal. He was also screened for vasculitis and hypercoagulable states [erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), lupus anticoagulant, antiphospholipid syndrome, antineutrophilic antibodies (ANA), factor V Leiden, antithrombin III, prothrombin mutation, level of protein C and S, level of homocysteine, thyroid-stimulating hormone (TSH)] but all reports were negative. On reanalyzing history, the patient had a habit of using xylometazoline (1 mg/ml) nasal spray 3–4 times a day for the last 5–6 years. It was prescribed to him before many years by a physician for an upper respiratory tract infection, but since then he had continued to use it continuously by purchasing it over the counter from local pharmacies. Thus, xylometazoline was considered to be the etiological factor for the cerebral vasospasm induced ischemic stroke in this case. The patient was advised to stop xylometazoline spray immediately and was treated with aspirin, clopidogrel, and statin for secondary prevention.
Figure 1: MRI brain showing left medullary infarct

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Figure 2: MRI brain showing left vertebral stenosis

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Ischemic stroke due to sympathomimetic drugs is a silent hidden healthcare problem. Though this association is relatively rare in the community, this association of stroke and sympathomimetic drug use is increasingly being described.[1],[2] Common sympathomimetic drugs like pseudoephedrine, phenylephrine (oral), and also xylometazoline, oxymetazoline, naphazoline, ephedrine, and tuaminoheptane (intranasal) are widely used over the counter (OTC) drugs in conditions like common cold, allergic rhinitis, sinusitis, and upper respiratory tract infection.[2] Common side effects of these drugs including xylometazoline are dryness, burning or stinging inside the nose, sneezing, runny nose whereas headache, dizziness, anxiety, palpitations, wheezing are some less pronounced side effects.[3] These OTC sympathomimetic drugs can also be an independent risk factor for ischemic and hemorrhagic stroke.[1]

There are many pathophysiological presumptions for a cerebrovascular accident in our case. One of them and the most presumable is the vasoconstriction of cerebral arteries. Xylometazoline is an imidazoline derivative that causes a reduction in nasal mucosal edema by directly acting on adrenergic receptors or indirectly releasing more potent vasoconstrictor norepinephrine (NE), which in turn potentiates adrenergic tone and causes vasospasm of cerebral arteries.[1] Adrenergic receptors are diffusely located in the vascular walls including cerebral vessels and they play a very crucial role in cerebral blood flow.[4] Adrenergic receptors are mainly categorized into alpha 1 receptors, alpha 2 receptors, and beta receptors.[5] Cerebral arteries contract in response to alpha-adrenergic agonist and this contraction can be blocked by alpha-adrenergic antagonist.[4] Sympathomimetic agents (epinephrine, NE, naphazoline, and xylometazoline) can control vascular tone and/or permeability in the central nervous system (CNS) and this can lead to blood pressure alterations and associated central nervous system complications.[5] Ischemic stroke in our patient could be due to reversible cerebral vasoconstriction syndrome (RCVS) secondary to xylometazoline mediated central adrenergic receptor stimulation. RCVS is defined as reversible vasospasm of intracerebral arteries mainly brought on by the disturbance in vascular tone.[6] It presents as a severe thunderclap headache with or without focal neurological deficits.[6] It is triggered by pregnancy and its complications (eclampsia, pre-eclampsia), sympathomimetic drugs (pseudoephedrine, oxymetazoline, xylometazoline), anti-depressants, illicit drug abuse, etc., Cerebral vasoconstriction in RCVS can lead to ischemic stroke (could be a mechanism in our case) and even intracerebral hemorrhage (intraparenchymal hemorrhage, sub-arachnoid hemorrhage) in some cases.[6]

The possible mechanism of hemorrhagic stroke due to sympathomimetic drugs is hypertensive crisis and vasculitis of the cerebral arteries which can also lead to subarachnoid and/or intracerebral hemorrhage.[1] Usage of phenylpropanolamine (nasal decongestant) has proven association with hemorrhagic stroke in 142 cases.[7] Phenylpropanolamine is used as appetite suppressants (in 16 cases) and common cold OTC medicine which leads to 22 cases of hemorrhagic stroke reported by the Food and Drug Administration (FDA).[8] Usage of naphazoline as nasal decongestant leads to hemorrhagic stroke in 1 case report with the possible mechanism of vasospasm or an increase in blood pressure.[9] It is presumable that the development of stroke would occur in a short interval of use or due to change in the pattern of dosage of sympathomimetic drugs. However, stroke has been described to occur after chronic use without any dosage modifications too as seen in our case. Leupold D, et al.*,[1] Costantino G, et al.*[9] and Cantu C, et al.*[10] reported patients developing stroke with chronic use of nasal sympathomimetic drugs without any change of pattern as in our case. Amongst the cases of stroke associated with nasal sympathomimetic drugs, hemorrhagic strokes have usually been described following acute short-term use while ischemic strokes have been described with chronic use. It can be postulated that acute sympathomimetic use may lead to accelerated hypertension/hypertensive crisis leading to intracerebral hemorrhage, while chronic use of these drugs may be leading to central adrenoreceptors dysfunction predisposing to chronic vasculopathy manifesting as ischemic stroke. Such focal vasculopathy of nasal mucosa has been described with nasal decongestant spray use leading to rebound nasal congestion on stopping the use and this has been postulated to lead to chronic continuous use of such nasal decongestants by the patients. This phenomenon of “rebound congestion” has been described as Rhinitis medicamentosa and occurs due to inflammation of the nasal mucosa caused primarily by the prolonged use (more than 7 to 10 days) of topical nasal decongestant.[11] There are 2 cases reported having brain infarction and 1 case having retinal artery occlusion due to chronic nasal use of oxymetazoline and presumed mechanism is arterial occlusion.[10] A French pharmacovigilance survey reported 52 cases of stroke in association with nasal decongestant use.[2] Other than the survey, other cases of stroke due to short and long term use of nasal sympathomimetic drugs have also been reported in the medical literature [Table 1]. All the cases of stroke have been reported with the usual therapeutic doses of sympathomimetic drugs and no dose-dependent effect has been reported making it pertinent to be aware of this association as stroke can have major devastating long-term sequelae for the patients.
Table 1: Case series of stroke reported because of nasal administration of sympathomimetic drugs

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Even in India, xylometazoline nasal sprays are easily available as OTC medicines. Use of OTC sympathomimetic nasal spray can be an independent risk factor for stroke and this should be considered in the evaluation of causes of stroke. The rare risk of stroke associated with sympathomimetic nasal sprays should also be discussed with patients before prescription of such therapy.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



[14]



 
   References Top

1.
Leupold D, Wartenberg KE. Xylometazoline abuse induced ischemic stroke in a young adult. Neurologist 2011;17:41-3.  Back to cited text no. 1
    
2.
Lafaurie M, Olivier P, Khouri C, Atzenhoffer M, Bihan K, Durrieu G, et al. Myocardial infarction and ischemic stroke with vasoconstrictors used as nasal decongestant for common cold: A French pharmacovigilance survey. Eur J Clin Pharmacol 2020;76:603-4.  Back to cited text no. 2
    
3.
Dokuyucu R, Gokce H, Sahan M, Sefil F, Tas ZA, Tutuk O, et al. Systemic side effects of locally used oxymetazoline. International journal of clinical and experimental medicine. 2015;8:2674-8.  Back to cited text no. 3
    
4.
Tsukahara T, Taniguchi T, Fujiwara M, Handa H, Nishikawa M. Alterations in alpha adrenergic receptors in human cerebral arteries after subarachnoid hemorrhage. Stroke 1985;16:53-8.  Back to cited text no. 4
    
5.
Nakai K, Itakura T, Naka Y, Nakakita K, Kamei I, Imai H, et al. The distribution of adrenergic receptors in cerebral blood vessels: An autoradiographic study. Brain Res 1986;381:148-52.  Back to cited text no. 5
    
6.
Dakay K, McTaggart RA, Jayaraman MV, Yaghi S, Wendell LC. Reversible cerebral vasoconstriction syndrome presenting as an isolated primary intraventricular hemorrhage. Chin Neurosurg J 2018;4:11.  Back to cited text no. 6
    
7.
Zavala JA, Pereira ER, Zétola VH, Teive HA, Nóvak ÉM, Werneck LC. Hemorrhagic stroke after naphazoline exposition: Case report. Arq Neuropsiquiatr 2004;62:889-91.  Back to cited text no. 7
    
8.
Kernan WN, Viscoli CM, Brass LM, Broderick JP, Brott T, Feldmann E, et al. Phenylpropanolamine and the risk of hemorrhagic stroke. N Engl J Med 2000;343:1826-32.  Back to cited text no. 8
    
9.
Costantino G, Ceriani E, Sandrone G, Montano N. Ischemic stroke in a man with naphazoline abuse history. Am J Emerg Med 2007;25:983.e1-2.  Back to cited text no. 9
    
10.
Cantu C, Arauz A, Murillo-Bonilla LM, López M, Barinagarrementeria F. Stroke associated with sympathomimetics contained in over-the-counter cough and cold drugs. Stroke 2003;34:1667-72.  Back to cited text no. 10
    
11.
Wahid NWB, Shermetaro C. Rhinitis Medicamentosa. [Updated 2019 Dec 28]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020. Available from: https://www.ncbi.nlm.nih.gov/books/NBK538318/.  Back to cited text no. 11
    
12.
Liguori C, Garaci F, Romigi A, Mercuri NB, Marciani MG, Placidi F. Bilateral thalamic stroke due to nasal ephedrine and naphazoline use. Neurol Sci 2015;36:1285-6.  Back to cited text no. 12
    
13.
Montalban J, Ibanez L, Rodriguez C, Lopez M, Sumalla J, Codina A. Cerebral infarction after excessive use of nasal decongestants. J Neurol Neurosurg Psychiatry 1989;52:541-3.  Back to cited text no. 13
    
14.
Magargal LE, Sanborn GE, Donoso LA, Gonder JR. Branch retinal artery occlusion after excessive use of nasal spray. Ann Ophthalmol 1985;17:500-1.  Back to cited text no. 14
    


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