- Email: [email protected]
Montelukast-induced metamorphopsia in a pediatric patient
Ann Allergy Asthma Immunol xxx (2016) 1e2
Contents lists available at ScienceDirect
Letter
Montelukast-induced metamorphopsia in a pediatric patient A case report and a pharmacovigilance database analysis Metamorphopsia is a type of optical illusion in which the size, shape, or angulation of objects is perceived as altered. Individuals typically see lines as wavy instead of straight and flat surfaces as curved. It is a rare manifestation of a central nervous system insult, mainly to the visual or vestibular systems.1 It is a symptom caused by disorders of the retina or choroid and frequently observed in age-related macular degeneration.1 Metamorphopsia rarely occurs as an adverse drug reaction (ADR). An analysis of case reports from the National Registry of Drug-Induced Ocular Side Effects has identified bisphosphonates, cetirizine, retinoids, and topiramate as the drugs mostly involved in ocular ADRs. No cases of metamorphopsia were detected,2 confirming the rarity of this ADR. To date, the ocular ADRs are not included in the adverse effects reported in the summary of product characteristics of montelukast; the correlation between its use and the ocular event has not yet been investigated. Montelukast is used in the treatment of asthma and allergic rhinitis in children and adults. Although generally well tolerated, it may lead to clinical ADRs, such as upper respiratory tract infection, worsening asthma, and headache. Rare events of eosinophilic granulomatosis with polyangiitis have also been reported.3 We present the first case, to our knowledge, of montelukast linked to the onset of metamorphopsia. We propose a possible mechanism leading to its insurgence and provide an analysis of international pharmacovigilance databases to map its occurrence. A 12-year-old girl with asthma was treated with montelukast at the therapeutic dose (5 mg/d). Approximately an hour after the first oral administration, the patient experienced headache and visual disturbance in which the perfectly straight lines appeared wavy and parts of the line appeared blank with flat surface bending. Approximately 15 minutes after the onset of the visual disturbance, she was hospitalized. Neurologic examination and electroencephalography revealed no abnormalities. Results of an Amsler test, a diagnostic tool used to detect the visual disturbances, were positive.4 The patient received no other concomitant drug or herbal treatment and had no personal or family history of ocular diseases. Considering the temporality between the drug intake and the appearance of the reaction, the treatment was discontinued, and a diagnosis of iatrogenic metamorphopsia was made. The ADR resolved after drug withdrawal in few days. The patient no longer
Disclosures: Authors have nothing to disclose. Funding Sources: This study was supported by the Italian Medicines Agency, the Centre of Pharmacovigilance of Regione Lombardia, and grant RC 2014 from the Italian Ministry of Health (Dr Clementi). Drs Clementi and Radice jointly directed this work.
experienced ocular disturbances and metamorphopsia during a 3-month follow-up. The positive dechallenge result and the temporal association between the drug’s use and the onset of the reaction suggested a possible causal relationship between metamorphopsia and montelukast administration, which was also confirmed by the causality assessment scale of Naranjo et al,5 the algorithm mostly used to identify the causality of ADR. Montelukast-associated metamorphopsia has not previously been reported in the literature, although the international pharmacovigilance databases contain several reports of ocular events associated with the drug. We retrieved 719 reports of ocular ADRs in which montelukast was the suspected drug involved, inserted into the following pharmacovigilance databases: the Danish Health and Medicines Authority, the Health Canada Vigilance Adverse Reaction Online Database, the Netherlands Pharmacovigilance Centre Lareb Databank, the UK Medicines and Healthcare Products Regulatory Agency, the US Food and Drug Administration Adverse Event Reporting System, and the Australian Adverse Event Reporting System (Table 1). Of 719 ocular ADR reports, 4 of those in the Adverse Event Reporting System described metamorphopsia, representing 0.5% of the total ocular events retrieved in our analysis. Of these, one refers of a 13-year-old boy with multiple allergies in therapy with montelukast. Approximately 15 minutes after the administration, the patient experienced visual disturbance with metamorphopsia. The limit of this analysis is that the pharmacovigilance databases mostly receive reports of serious ADRs, resulting in an underestimation of the issue. The ocular ADRs are scant in general and rare with montelukast. Previous studies have estimated that myopia and conjunctivitis can occur in patients taking montelukast, with an incidence of 2%; mydriasis is among the most frequent adverse effects with overdosage of the drug. The pathogenic causes of montelukast-associated metamorphopsia may be multiple and not necessarily mutually exclusive. Metamorphopsia is often the result of progressive accumulation of fluid in the rear area of the ocular fundus, leading to the perception of a deformed visual field.1 It is therefore plausible that inflammation and peripheral edema play an important role in this visual disturbance.6 Inflammatory processes and the increase in vascular permeability are indeed responsible for macular edema that results in metamorphopsia. The release of inflammatory mediators, such as histamine and products of arachidonic acid metabolism, has been demonstrated in the bronchoalveolar fluid of patients with asthma, and in some cases montelukast is able to cause periorbital edema.7 In our case, a partial inefficacy of montelukast in reducing proinflammatory mediators combined with the onset of edema have probably triggered metamorphopsia. Another possibility is headache often associated with bizarre visual and spatial distortions.8
http://dx.doi.org/10.1016/j.anai.2016.01.013 1081-1206/Ó 2016 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
2
Letter / Ann Allergy Asthma Immunol xxx (2016) 1e2
Table 1 Ocular ADRs in Which Montelukast Was Involved as the Suspected Drug and Inserted Into the International Pharmacovigilance Databases Pharmacovigilance database
No. of ADR reports belonging to SOC eye disorder
No. of reports of metamorphopsia
Most commonly reported ADRs belong to SOC eye disorder
Period of observation
Xerophthalmia, blepharospasm, eye swelling, periorbital edema,a eye pruritus, pupillary disorder, retinal deposits, visual impairment visual impairment, blindness transient, hyperhidrosis, periorbital edema, blepharospasm, cough,a drug ineffectivea pyrexia,a somnolence,a dry eye, excessive eye blinking, eye movement disorder Conjunctival hemorrhage, dry eye, visual impairment, lacrimal disorder, vision blurred Cataract, eye disorder periorbital edema, eye pain, eye movement disorder, mydriasis, photopsia vision blurred, visual impairment Photopsia, eye disorder, dry eye, periorbital edema, dizziness,a visual impairment, headache,a nausea,a anxiety,a vision blurred, visual disturbance, vision blurred, cataract, paraesthesia, visual field defect, eye pain Headache,a migraine,a nausea,a visual impairment, periorbital edema, dizziness,a fatigue,a vomiting,a photopsia, visual field defect, peripheral edemaa
1998e2015
Danish Health and Medicines Authority
11
NR
Health Canada Vigilance Adverse Reaction Online Database
18
NR
Netherlands Pharmacovigilance Centre Lareb Databank UK Medicines and Healthcare products Regulatory Agency
11
NR
62
NR
AERS
DAEN
Total
611
6
719
4
NR
1998e2015
1998e2015 1998e2015
2004e2012
1998e2015
4
Abbreviations: ADR, adverse drug reaction; AERS, Adverse Event Reporting System; DAEN, Australian Adverse Event Reporting System; NR, not reported; SOC, system organ class. a ADRs reported in association with ocular ADRs.
Headache has been commonly reported (>1 per 100 to <1 per 10) in clinical studies that enrolled patients with asthma treated with montelukast, as well as in our case. Moreover, in our analysis, the ocular ADR reports have frequently involved the headache and migraine, probably resulting in the predisposition of visual disturbance. Finally, metamorphopsia can also be caused by psychiatric disorders, often detected in patients with asthma. Montelukast can rarely cause psychiatric ADR, including visual hallucinations.9 It has been suggested that the inhibition of leukotriene receptors in the brain could be responsible for these neuropsychiatric ADRs. Interestingly, montelukast was associated with the Alice-in-Wonderland syndrome, which associated disorienting neurologic conditions with metamorphopsia. In addition, in this case, no obvious trigger and negative magnetic resonance imaging and electroencephalography results were reported.10 Our case report and previous data from the literature and the international pharmacovigilance databases identify a possible montelukast-associated ADR in metamorphopsia and provide a rationale for its occurrence. These results provide means to help physicians identify possible correlations between ocular adverse effects and montelukast for a prompt identification. Increased attention in pharmacovigilance to this ADR appears relevant because of the wide pediatric use of montelukast. Carla Carnovale, PharmaD* Marta Gentili, PharmaD* Stefania Antoniazzi, PharmaD*,y Sonia Radice, BioID* Emilio Clementi, MD, PhDz,x *Unit of Clinical Pharmacology Department of Biomedical and Clinical Sciences University Hospital “Luigi Sacco” Università di Milano y Scientific Direction IRCCS Foundation Ca’ Granda Ospedale Maggiore Policlinico Milan, Italy
z
Scientific Institute IRCCS E. Medea Bosisio Parini Lecco, Italy x Unit of Clinical Pharmacology Department of Biomedical and Clinical Sciences Consiglio Nazionale delle Ricerche Institute of Neuroscience University Hospital “Luigi Sacco” Università di Milano Milan, Italy [email protected]
References [1] Walsh FB, Hoyt WF. Clinical Neuro-ophthalmology, 1. Baltimore, MD: Williams & Wilkins; 1969:753e754. [2] Fraunfelder FW, Fraunfelder FT. Adverse ocular drug reactions recently identified by the National Registry of Drug-Induced Ocular Side Effects. Ophthalmology. 2004;111:1275e1279. [3] Giusti Del Giardino L, Cavallaro T, Anzola GP, Lombardi C, Ferrari S. Neuropathy in eosinophilic granulomatosis with polyangiitis: a comparison study of 24 cases with or without prior leukotriene antagonist exposure. Eur Ann Allergy Clin Immunol. 2014;46:201e209. [4] Amsler M. L’Examen qualitatif de la fonction maculaire. Ophthalmologica. 1947;114:248e261. [5] Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981;30:239e245. [6] Crawford CM, Igboeli O. A review of the inflammatory chorioretinopathies: the white dot syndromes. ISRN Inflamm. 2013;2013:783190. [7] Geller M. Marked peripheral edema associated with montelukast and prednisone. Ann Intern Med. 2000;132:924. [8] Koyama M, Mizota A, Igarashi Y, Adachi-Usami E. Seventeen cases of central serous chorioretinopathy associated with systemic corticosteroid therapy. Ophthalmologica. 2004;218:107e110. [9] Wallerstedt SM, Brunlof G, Sundstrom A, Eriksson AL. Montelukast and psychiatric disorders in children. Pharmacoepidemiol Drug Saf. 2009;18: 858e864. [10] Bernal Vañó E, López Andrés N. A case of Alice-in-Wonderland syndrome probably associated with the use of montelukast. Ann Pediatr. 2013;78: 127e128.
Contents lists available at ScienceDirect
Letter
Montelukast-induced metamorphopsia in a pediatric patient A case report and a pharmacovigilance database analysis Metamorphopsia is a type of optical illusion in which the size, shape, or angulation of objects is perceived as altered. Individuals typically see lines as wavy instead of straight and flat surfaces as curved. It is a rare manifestation of a central nervous system insult, mainly to the visual or vestibular systems.1 It is a symptom caused by disorders of the retina or choroid and frequently observed in age-related macular degeneration.1 Metamorphopsia rarely occurs as an adverse drug reaction (ADR). An analysis of case reports from the National Registry of Drug-Induced Ocular Side Effects has identified bisphosphonates, cetirizine, retinoids, and topiramate as the drugs mostly involved in ocular ADRs. No cases of metamorphopsia were detected,2 confirming the rarity of this ADR. To date, the ocular ADRs are not included in the adverse effects reported in the summary of product characteristics of montelukast; the correlation between its use and the ocular event has not yet been investigated. Montelukast is used in the treatment of asthma and allergic rhinitis in children and adults. Although generally well tolerated, it may lead to clinical ADRs, such as upper respiratory tract infection, worsening asthma, and headache. Rare events of eosinophilic granulomatosis with polyangiitis have also been reported.3 We present the first case, to our knowledge, of montelukast linked to the onset of metamorphopsia. We propose a possible mechanism leading to its insurgence and provide an analysis of international pharmacovigilance databases to map its occurrence. A 12-year-old girl with asthma was treated with montelukast at the therapeutic dose (5 mg/d). Approximately an hour after the first oral administration, the patient experienced headache and visual disturbance in which the perfectly straight lines appeared wavy and parts of the line appeared blank with flat surface bending. Approximately 15 minutes after the onset of the visual disturbance, she was hospitalized. Neurologic examination and electroencephalography revealed no abnormalities. Results of an Amsler test, a diagnostic tool used to detect the visual disturbances, were positive.4 The patient received no other concomitant drug or herbal treatment and had no personal or family history of ocular diseases. Considering the temporality between the drug intake and the appearance of the reaction, the treatment was discontinued, and a diagnosis of iatrogenic metamorphopsia was made. The ADR resolved after drug withdrawal in few days. The patient no longer
Disclosures: Authors have nothing to disclose. Funding Sources: This study was supported by the Italian Medicines Agency, the Centre of Pharmacovigilance of Regione Lombardia, and grant RC 2014 from the Italian Ministry of Health (Dr Clementi). Drs Clementi and Radice jointly directed this work.
experienced ocular disturbances and metamorphopsia during a 3-month follow-up. The positive dechallenge result and the temporal association between the drug’s use and the onset of the reaction suggested a possible causal relationship between metamorphopsia and montelukast administration, which was also confirmed by the causality assessment scale of Naranjo et al,5 the algorithm mostly used to identify the causality of ADR. Montelukast-associated metamorphopsia has not previously been reported in the literature, although the international pharmacovigilance databases contain several reports of ocular events associated with the drug. We retrieved 719 reports of ocular ADRs in which montelukast was the suspected drug involved, inserted into the following pharmacovigilance databases: the Danish Health and Medicines Authority, the Health Canada Vigilance Adverse Reaction Online Database, the Netherlands Pharmacovigilance Centre Lareb Databank, the UK Medicines and Healthcare Products Regulatory Agency, the US Food and Drug Administration Adverse Event Reporting System, and the Australian Adverse Event Reporting System (Table 1). Of 719 ocular ADR reports, 4 of those in the Adverse Event Reporting System described metamorphopsia, representing 0.5% of the total ocular events retrieved in our analysis. Of these, one refers of a 13-year-old boy with multiple allergies in therapy with montelukast. Approximately 15 minutes after the administration, the patient experienced visual disturbance with metamorphopsia. The limit of this analysis is that the pharmacovigilance databases mostly receive reports of serious ADRs, resulting in an underestimation of the issue. The ocular ADRs are scant in general and rare with montelukast. Previous studies have estimated that myopia and conjunctivitis can occur in patients taking montelukast, with an incidence of 2%; mydriasis is among the most frequent adverse effects with overdosage of the drug. The pathogenic causes of montelukast-associated metamorphopsia may be multiple and not necessarily mutually exclusive. Metamorphopsia is often the result of progressive accumulation of fluid in the rear area of the ocular fundus, leading to the perception of a deformed visual field.1 It is therefore plausible that inflammation and peripheral edema play an important role in this visual disturbance.6 Inflammatory processes and the increase in vascular permeability are indeed responsible for macular edema that results in metamorphopsia. The release of inflammatory mediators, such as histamine and products of arachidonic acid metabolism, has been demonstrated in the bronchoalveolar fluid of patients with asthma, and in some cases montelukast is able to cause periorbital edema.7 In our case, a partial inefficacy of montelukast in reducing proinflammatory mediators combined with the onset of edema have probably triggered metamorphopsia. Another possibility is headache often associated with bizarre visual and spatial distortions.8
http://dx.doi.org/10.1016/j.anai.2016.01.013 1081-1206/Ó 2016 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
2
Letter / Ann Allergy Asthma Immunol xxx (2016) 1e2
Table 1 Ocular ADRs in Which Montelukast Was Involved as the Suspected Drug and Inserted Into the International Pharmacovigilance Databases Pharmacovigilance database
No. of ADR reports belonging to SOC eye disorder
No. of reports of metamorphopsia
Most commonly reported ADRs belong to SOC eye disorder
Period of observation
Xerophthalmia, blepharospasm, eye swelling, periorbital edema,a eye pruritus, pupillary disorder, retinal deposits, visual impairment visual impairment, blindness transient, hyperhidrosis, periorbital edema, blepharospasm, cough,a drug ineffectivea pyrexia,a somnolence,a dry eye, excessive eye blinking, eye movement disorder Conjunctival hemorrhage, dry eye, visual impairment, lacrimal disorder, vision blurred Cataract, eye disorder periorbital edema, eye pain, eye movement disorder, mydriasis, photopsia vision blurred, visual impairment Photopsia, eye disorder, dry eye, periorbital edema, dizziness,a visual impairment, headache,a nausea,a anxiety,a vision blurred, visual disturbance, vision blurred, cataract, paraesthesia, visual field defect, eye pain Headache,a migraine,a nausea,a visual impairment, periorbital edema, dizziness,a fatigue,a vomiting,a photopsia, visual field defect, peripheral edemaa
1998e2015
Danish Health and Medicines Authority
11
NR
Health Canada Vigilance Adverse Reaction Online Database
18
NR
Netherlands Pharmacovigilance Centre Lareb Databank UK Medicines and Healthcare products Regulatory Agency
11
NR
62
NR
AERS
DAEN
Total
611
6
719
4
NR
1998e2015
1998e2015 1998e2015
2004e2012
1998e2015
4
Abbreviations: ADR, adverse drug reaction; AERS, Adverse Event Reporting System; DAEN, Australian Adverse Event Reporting System; NR, not reported; SOC, system organ class. a ADRs reported in association with ocular ADRs.
Headache has been commonly reported (>1 per 100 to <1 per 10) in clinical studies that enrolled patients with asthma treated with montelukast, as well as in our case. Moreover, in our analysis, the ocular ADR reports have frequently involved the headache and migraine, probably resulting in the predisposition of visual disturbance. Finally, metamorphopsia can also be caused by psychiatric disorders, often detected in patients with asthma. Montelukast can rarely cause psychiatric ADR, including visual hallucinations.9 It has been suggested that the inhibition of leukotriene receptors in the brain could be responsible for these neuropsychiatric ADRs. Interestingly, montelukast was associated with the Alice-in-Wonderland syndrome, which associated disorienting neurologic conditions with metamorphopsia. In addition, in this case, no obvious trigger and negative magnetic resonance imaging and electroencephalography results were reported.10 Our case report and previous data from the literature and the international pharmacovigilance databases identify a possible montelukast-associated ADR in metamorphopsia and provide a rationale for its occurrence. These results provide means to help physicians identify possible correlations between ocular adverse effects and montelukast for a prompt identification. Increased attention in pharmacovigilance to this ADR appears relevant because of the wide pediatric use of montelukast. Carla Carnovale, PharmaD* Marta Gentili, PharmaD* Stefania Antoniazzi, PharmaD*,y Sonia Radice, BioID* Emilio Clementi, MD, PhDz,x *Unit of Clinical Pharmacology Department of Biomedical and Clinical Sciences University Hospital “Luigi Sacco” Università di Milano y Scientific Direction IRCCS Foundation Ca’ Granda Ospedale Maggiore Policlinico Milan, Italy
z
Scientific Institute IRCCS E. Medea Bosisio Parini Lecco, Italy x Unit of Clinical Pharmacology Department of Biomedical and Clinical Sciences Consiglio Nazionale delle Ricerche Institute of Neuroscience University Hospital “Luigi Sacco” Università di Milano Milan, Italy [email protected]
References [1] Walsh FB, Hoyt WF. Clinical Neuro-ophthalmology, 1. Baltimore, MD: Williams & Wilkins; 1969:753e754. [2] Fraunfelder FW, Fraunfelder FT. Adverse ocular drug reactions recently identified by the National Registry of Drug-Induced Ocular Side Effects. Ophthalmology. 2004;111:1275e1279. [3] Giusti Del Giardino L, Cavallaro T, Anzola GP, Lombardi C, Ferrari S. Neuropathy in eosinophilic granulomatosis with polyangiitis: a comparison study of 24 cases with or without prior leukotriene antagonist exposure. Eur Ann Allergy Clin Immunol. 2014;46:201e209. [4] Amsler M. L’Examen qualitatif de la fonction maculaire. Ophthalmologica. 1947;114:248e261. [5] Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981;30:239e245. [6] Crawford CM, Igboeli O. A review of the inflammatory chorioretinopathies: the white dot syndromes. ISRN Inflamm. 2013;2013:783190. [7] Geller M. Marked peripheral edema associated with montelukast and prednisone. Ann Intern Med. 2000;132:924. [8] Koyama M, Mizota A, Igarashi Y, Adachi-Usami E. Seventeen cases of central serous chorioretinopathy associated with systemic corticosteroid therapy. Ophthalmologica. 2004;218:107e110. [9] Wallerstedt SM, Brunlof G, Sundstrom A, Eriksson AL. Montelukast and psychiatric disorders in children. Pharmacoepidemiol Drug Saf. 2009;18: 858e864. [10] Bernal Vañó E, López Andrés N. A case of Alice-in-Wonderland syndrome probably associated with the use of montelukast. Ann Pediatr. 2013;78: 127e128.