http://informahealthcare.com/cot ISSN: 1556-9527 (print), 1556-9535 (electronic) Cutan Ocul Toxicol, Early Online: 1–3 ! 2015 Informa Healthcare USA, Inc. DOI: 10.3109/15569527.2015.1020544
CASE REPORT
Voriconazole-associated visual disturbances and hallucinations Gulsum Iclal Bayhan1, Mesut Garipardic2, Kamuran Karaman2, and Sinan Akbayram2 Department of Pediatric Infectious Disease and 2Department of Pediatric Hematology, Dursun Odabas Medical Center, Yuzuncu Yil University, Van, Turkey
Cutaneous and Ocular Toxicology Downloaded from informahealthcare.com by Kainan University on 04/06/15 For personal use only.
1
Abstract
Keywords
Voriconazole is a second-generation azole widely used for the prevention and treatment of fungal infection in leukemia patients. Voriconazole is considered the primary antifungal agent for invasive aspergillosis. We report a case of 16-year-old girl who developed visual disturbance and visual and auditory hallucinations after intravenous voriconazole treatment for invasive pulmonary aspergillosis. Due to the visual hallucinations and visual disturbance began acutely and shortly after the initiation of voriconazole, and no other cause could be determined, the symptoms were considered to be the side effects of voriconazole. Simultaneous development of visual side effects and hallucinations rarely have been reported before.
Color discrimination, hallucinations, visual disturbance, voriconazole
Introduction Voriconazole is the primary antifungal agent recommended for treating invasive pulmonary aspergillosis in neutropenic patients. Voriconazole is associated with several side effects, including visual and neurological adverse reactions. Herein we reported a girl treated with voriconazole for invasive pulmonary aspergillosis that developed visual disturbance and visual and auditory hallucinations.
Case A 16-year-old girl presented to an outlying hospital with a 15-day history of fever, sore throat, and swollen glands in the neck. She was prescribed antibiotics, but her complaints persisted. Physical examination showed that she had cryptic tonsillitis and bilateral supraclavicular lymphadenitis. There was hepatomegaly 4 cm below the costal margin. Traube’s space was closed and the spleen was 1–2 cm palpable under the costa. Blood analysis was significant only for anemia (hemoglobin ¼ 7.3 g/dL). Atypical lymphocytes were noted via peripheral blood smear. Due to abnormal physical examination findings, anemia, and presence of atypical lymphocytes, bone marrow aspiration was performed, and histopathological analysis of the sample showed hypercellular bone marrow with 99% monotypic lymphoblastic cells. The patient was diagnosed with T-cell leukemia based on immunohistochemical and flow cytometric examinations. She was hospitalized and the Turk ALL BFM 2000 for high-risk group protocol was
Address for correspondence: Dr Gulsum Iclal Bayhan, Department of Pediatric Infectious Disease, Dursun Odabas Medical Center, Yuzuncu Yil University, Van, Turkey. E-mail: [email protected]
History Received 23 December 2014 Revised 8 February 2015 Accepted 14 February 2015 Published online 23 March 2015
subsequently initiated. Induction phase of this protocol which consists of prednisolone, vincristine, daunorubicin, L -asparaginase, and intrathecal methotrexate were given. On 33th day of the induction phase of chemotherapy, she had episodes of febrile neutropenia and meropenem treatment was commenced. Due to severe neutropenia (absolute neutrophil count5100/mm3) and persistent fever, vancomycin and caspofungin were added to her treatment. One month later, the patient again became febrile when she was neutropenic and within a few days progressive respiratory distress developed. Physical examination showed that respiratory sounds were decreased and there were bilateral crepitant rales. Chest X-ray showed consolidation in the lower lobes of both lungs. Chest CT findings indicated invasive pulmonary aspergillosis and galactomannan was positive. Caspofungin was withdrawn and intravenous voriconazole 2 400 mg/dose was started (her body weight was 55 kg). On day 4 of voriconazole treatment she developed visual and auditory hallucinations and disturbance. She said that she was seeing strangers who were walking around her room and talking with her. She also reported yellow and green discoloration and that she saw bright yellow-green lights for 4–5 minutes several times a day. Onset of this phenomenon was sudden. Her orientation and consciousness were normal. She did not have a history of previous psychiatric illness and similar symptoms. She did not have any metabolic abnormalities that could have caused these symptoms. Ophthalmologic examination was normal and cranial MRG was normal. As the visual hallucinations and visual disturbance began acutely and shortly after the initiation of voriconazole, and no other neurological, ophthalmological and metabolic causes could be determined, the symptoms were considered to be the side effects of voriconazole. Naranjo Adverse Drug Reaction Probability Scale was performed to assess whether there was a
2
G. I. Bayhan et al.
causal relationship between voriconazole and patient’s symptoms1. The score was found 5, which referred to probable relationship. Her antifungal therapy could not be changed because of her serious invasive pulmonary aspergillosis. Voriconazole was continued and the symptoms persisted for consecutive 4 days, then they disappeared completely. She took voriconazole for 70 days and the voriconazole-induced adverse effects did not recur.
Cutaneous and Ocular Toxicology Downloaded from informahealthcare.com by Kainan University on 04/06/15 For personal use only.
Discussion Voriconazole is a second-generation azole widely used for the prevention and treatment of fungal infection in leukemia patients. Voriconazole is considered the primary antifungal agent for invasive aspergillosis, according to IDSA 2008 guidelines2. Voriconazole is generally well-tolerated and its adverse effects include hepatotoxicity, skin rashes, arrhythmia, bone morrow depression, and visual and neurological disturbances3,4. Fever, hypoxia, severe metabolic disturbances, liver failure, renal failure, neurological disease, temporal lobe epilepsy, and cerebral tumor can cause visual disturbance and hallucinatons5. In our patient, all these factors were excluded. Among the drugs of Turk ALL BFM 2000, only prednisolone can cause this clinical state. Although our patient was under chemotherapy for more than two months, 4 days after the initiation of voriconazole, visual disturbance and hallucinations appeared. Therefore, the side effects were attributed to voriconazole. Voriconazole-associated visual toxicity includes altered color discrimination, blurred vision, photophobia, optic neuritis, episcleritis, and scleritis3,4,6. Neurological adverse events associated with voriconazole include painful peripheral neuropathy, hemiplegia, paresthesia, seizure, nystagmus, dysarthria, auditory hallucinations, visual hallucinations, confusion, disorientation, anxiety, agitation, irritability, impaired concentration, insomnia, hypotonia, asthenia, tremor, and delirium3,4,6. In those treated with voriconazole, the incidence of hallucinations was reported to be 16.6%, versus 4–35% for visual adverse events7,8. Hallucination is commonly co-morbid with visual disturbance9. The mechanism of visual disturbance accompanied by hallucination due to voriconazole is not yet fully known. Voriconazole accumulates at a high concentration in cerebrospinal fluid and cerebral tissue6,9. This affinity may affect the retina and central nervous system influenced by serum voriconazole levels9. It has been reported that the voriconazole plasma concentrations are associated with elevated liver enzymes, and visual and neurological adverse effects3,10. Monitoring the serum voriconazole level during its therapeutic administration is recommended for improving treatment outcome and preventing/minimizing adverse reactions11. In a study, a total of 176 voriconazole level were measured in 26 patients and a significant relationship for every 0.1 mg/ml increase in the serum voriconazole level and the occurrence of neurological adverse reaction has been demonstrated. Authors concluded that serum voriconazole level can be used to identify patients at high risk for the development of neurological
Cutan Ocul Toxicol, Early Online: 1–3
adverse events3. All the patients with a serum voriconazole level 45.5 mg/mL developed neurological adverse effect, whereas only 2 patients with a serum voriconazole level 55.5 mg/mL had neurological adverse reactions3. It was reported that monitorization of the serum voriconazole level significantly reduced the occurrence of drug cessation due to adverse events12. The optimal therapeutic serum level has not been determined with certainty, but generally 1–6 mg/mL is recommended11. The serum voriconazole level could not be monitored in the presented patient because the test was not available at our hospital. According to the literature, voriconazole treatment is generally withdrawn when neurological and visual adverse effects develop, and symptoms were reported to disappear 24 hours–2 weeks after voriconazole cessation without any residue or sequel3,4,6,7. However, many patients must remain on the medication. It was reported that when the intravenous route of voriconazole administration is switched to the oral route due to the development of visual or neurological disturbances, such side effects generally disappear7. Continuation of oral voriconazole treatment is recommended in critical-condition patients7. In addition, there are reports of cases that developed neurological adverse reactions to voriconazole that improved spontaneously during ongoing treatment, as did the presented case3. In the presented patient, voriconazole could not be withdrawn or changed from the intravenous to the oral route because the patient had severe pulmonary aspergillosis and voriconazole treatment had been administered for only 4 days when the adverse effects developed; nonetheless, the symptoms resolved completely 4 days later. In conclusion, clinicians must be aware that voriconazole can cause visual disturbance and hallucinations. The differential diagnosis of visual disturbance is easier in cases accompanied by hallucination. Management of voriconazoleassociated visual and neurological toxicity includes discontinuation of the drug. Patients improve rapidly without sequelae after discontinuation of voriconazole, but cessation of treatment is not always necessary, as in some cases voriconazole-induced adverse effects resolve spontaneously while the treatment continues.
Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.
References 1. U.S. National Library of Medicine. http://livertox.nih.gov/ Narajo.html [last accessed 1 Feb 2015]. 2. Freifeld AG, Bow EJ, Sepkowitz KA, et al.; Infectious Diseases Society of America. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the infectious Diseases Society of America. Clin Infect Dis 2011;52:56–93. 3. Imhof A, Schaer DJ, Schanz U, Schwarz U. Neurological adverse events to voriconazole: evidence for therapeutic drug monitoring. Swiss Med Wkly 2006;136:739–742. 4. Eiden C, Peyrie`re H, Cociglio M, et al. Adverse effects of voriconazole: analysis of the French Pharmacovigilance Database. Ann Pharmacother 2007;41:755–763.
DOI: 10.3109/15569527.2015.1020544
Cutaneous and Ocular Toxicology Downloaded from informahealthcare.com by Kainan University on 04/06/15 For personal use only.
¨ sto¨r AJK. Hallucinations. In: Raftery AT, Lim 5. Raftery AT, Lim E, O ¨ sto¨r AJK, eds. Churchill’s pocketbook of differential diagnosis. E, O New York: Churchill Livingstone Elsevier; 2014:213–215. 6. Pasqualotto AC, Xavier MO, Andreolla HF, Linden R. Voriconazole therapeutic drug monitoring: focus on safety. Expert Opin Drug Saf 2010;9:125–137. 7. Zonios DI, Gea-Banacloche J, Childs R, Bennett JE. Hallucinations during voriconazole therapy. Clin Infect Dis 2008;47:e7–e10. 8. Zrenner E, Tomaszewski K, Hamlin J, et al. Effects of multiple doses of voriconazole on the vision of healthy volunteers: a doubleblind, placebo-controlled study. Ophthalmic Res 2014;52:43–52.
Voriconazole side effects
3
9. Imataki O, Ohnishi H, Kitanaka A, et al. Visual disturbance comorbid with hallucination caused by voriconazole in the Japanese population. Int J Hematol 2008;88:3–6. 10. Boyd AE, Modi S, Howard SJ, et al. Adverse reactions to voriconazole. Clin Infect Dis 2004;39:1241–1244. 11. Choi SH, Lee SY, Hwang JY, et al. Importance of voriconazole therapeutic drug monitoring in pediatric cancer patients with invasive aspergillosis. Pediatr Blood Cancer 2013;60:82–87. 12. Park WB, Kim NH, Kim KH, et al. The effect of therapeutic drug monitoring on safety and efficacy of voriconazole in invasive fungal infections: a randomized controlled trial. Clin Infect Dis 2012;55:1080–1087.
CASE REPORT
Voriconazole-associated visual disturbances and hallucinations Gulsum Iclal Bayhan1, Mesut Garipardic2, Kamuran Karaman2, and Sinan Akbayram2 Department of Pediatric Infectious Disease and 2Department of Pediatric Hematology, Dursun Odabas Medical Center, Yuzuncu Yil University, Van, Turkey
Cutaneous and Ocular Toxicology Downloaded from informahealthcare.com by Kainan University on 04/06/15 For personal use only.
1
Abstract
Keywords
Voriconazole is a second-generation azole widely used for the prevention and treatment of fungal infection in leukemia patients. Voriconazole is considered the primary antifungal agent for invasive aspergillosis. We report a case of 16-year-old girl who developed visual disturbance and visual and auditory hallucinations after intravenous voriconazole treatment for invasive pulmonary aspergillosis. Due to the visual hallucinations and visual disturbance began acutely and shortly after the initiation of voriconazole, and no other cause could be determined, the symptoms were considered to be the side effects of voriconazole. Simultaneous development of visual side effects and hallucinations rarely have been reported before.
Color discrimination, hallucinations, visual disturbance, voriconazole
Introduction Voriconazole is the primary antifungal agent recommended for treating invasive pulmonary aspergillosis in neutropenic patients. Voriconazole is associated with several side effects, including visual and neurological adverse reactions. Herein we reported a girl treated with voriconazole for invasive pulmonary aspergillosis that developed visual disturbance and visual and auditory hallucinations.
Case A 16-year-old girl presented to an outlying hospital with a 15-day history of fever, sore throat, and swollen glands in the neck. She was prescribed antibiotics, but her complaints persisted. Physical examination showed that she had cryptic tonsillitis and bilateral supraclavicular lymphadenitis. There was hepatomegaly 4 cm below the costal margin. Traube’s space was closed and the spleen was 1–2 cm palpable under the costa. Blood analysis was significant only for anemia (hemoglobin ¼ 7.3 g/dL). Atypical lymphocytes were noted via peripheral blood smear. Due to abnormal physical examination findings, anemia, and presence of atypical lymphocytes, bone marrow aspiration was performed, and histopathological analysis of the sample showed hypercellular bone marrow with 99% monotypic lymphoblastic cells. The patient was diagnosed with T-cell leukemia based on immunohistochemical and flow cytometric examinations. She was hospitalized and the Turk ALL BFM 2000 for high-risk group protocol was
Address for correspondence: Dr Gulsum Iclal Bayhan, Department of Pediatric Infectious Disease, Dursun Odabas Medical Center, Yuzuncu Yil University, Van, Turkey. E-mail: [email protected]
History Received 23 December 2014 Revised 8 February 2015 Accepted 14 February 2015 Published online 23 March 2015
subsequently initiated. Induction phase of this protocol which consists of prednisolone, vincristine, daunorubicin, L -asparaginase, and intrathecal methotrexate were given. On 33th day of the induction phase of chemotherapy, she had episodes of febrile neutropenia and meropenem treatment was commenced. Due to severe neutropenia (absolute neutrophil count5100/mm3) and persistent fever, vancomycin and caspofungin were added to her treatment. One month later, the patient again became febrile when she was neutropenic and within a few days progressive respiratory distress developed. Physical examination showed that respiratory sounds were decreased and there were bilateral crepitant rales. Chest X-ray showed consolidation in the lower lobes of both lungs. Chest CT findings indicated invasive pulmonary aspergillosis and galactomannan was positive. Caspofungin was withdrawn and intravenous voriconazole 2 400 mg/dose was started (her body weight was 55 kg). On day 4 of voriconazole treatment she developed visual and auditory hallucinations and disturbance. She said that she was seeing strangers who were walking around her room and talking with her. She also reported yellow and green discoloration and that she saw bright yellow-green lights for 4–5 minutes several times a day. Onset of this phenomenon was sudden. Her orientation and consciousness were normal. She did not have a history of previous psychiatric illness and similar symptoms. She did not have any metabolic abnormalities that could have caused these symptoms. Ophthalmologic examination was normal and cranial MRG was normal. As the visual hallucinations and visual disturbance began acutely and shortly after the initiation of voriconazole, and no other neurological, ophthalmological and metabolic causes could be determined, the symptoms were considered to be the side effects of voriconazole. Naranjo Adverse Drug Reaction Probability Scale was performed to assess whether there was a
2
G. I. Bayhan et al.
causal relationship between voriconazole and patient’s symptoms1. The score was found 5, which referred to probable relationship. Her antifungal therapy could not be changed because of her serious invasive pulmonary aspergillosis. Voriconazole was continued and the symptoms persisted for consecutive 4 days, then they disappeared completely. She took voriconazole for 70 days and the voriconazole-induced adverse effects did not recur.
Cutaneous and Ocular Toxicology Downloaded from informahealthcare.com by Kainan University on 04/06/15 For personal use only.
Discussion Voriconazole is a second-generation azole widely used for the prevention and treatment of fungal infection in leukemia patients. Voriconazole is considered the primary antifungal agent for invasive aspergillosis, according to IDSA 2008 guidelines2. Voriconazole is generally well-tolerated and its adverse effects include hepatotoxicity, skin rashes, arrhythmia, bone morrow depression, and visual and neurological disturbances3,4. Fever, hypoxia, severe metabolic disturbances, liver failure, renal failure, neurological disease, temporal lobe epilepsy, and cerebral tumor can cause visual disturbance and hallucinatons5. In our patient, all these factors were excluded. Among the drugs of Turk ALL BFM 2000, only prednisolone can cause this clinical state. Although our patient was under chemotherapy for more than two months, 4 days after the initiation of voriconazole, visual disturbance and hallucinations appeared. Therefore, the side effects were attributed to voriconazole. Voriconazole-associated visual toxicity includes altered color discrimination, blurred vision, photophobia, optic neuritis, episcleritis, and scleritis3,4,6. Neurological adverse events associated with voriconazole include painful peripheral neuropathy, hemiplegia, paresthesia, seizure, nystagmus, dysarthria, auditory hallucinations, visual hallucinations, confusion, disorientation, anxiety, agitation, irritability, impaired concentration, insomnia, hypotonia, asthenia, tremor, and delirium3,4,6. In those treated with voriconazole, the incidence of hallucinations was reported to be 16.6%, versus 4–35% for visual adverse events7,8. Hallucination is commonly co-morbid with visual disturbance9. The mechanism of visual disturbance accompanied by hallucination due to voriconazole is not yet fully known. Voriconazole accumulates at a high concentration in cerebrospinal fluid and cerebral tissue6,9. This affinity may affect the retina and central nervous system influenced by serum voriconazole levels9. It has been reported that the voriconazole plasma concentrations are associated with elevated liver enzymes, and visual and neurological adverse effects3,10. Monitoring the serum voriconazole level during its therapeutic administration is recommended for improving treatment outcome and preventing/minimizing adverse reactions11. In a study, a total of 176 voriconazole level were measured in 26 patients and a significant relationship for every 0.1 mg/ml increase in the serum voriconazole level and the occurrence of neurological adverse reaction has been demonstrated. Authors concluded that serum voriconazole level can be used to identify patients at high risk for the development of neurological
Cutan Ocul Toxicol, Early Online: 1–3
adverse events3. All the patients with a serum voriconazole level 45.5 mg/mL developed neurological adverse effect, whereas only 2 patients with a serum voriconazole level 55.5 mg/mL had neurological adverse reactions3. It was reported that monitorization of the serum voriconazole level significantly reduced the occurrence of drug cessation due to adverse events12. The optimal therapeutic serum level has not been determined with certainty, but generally 1–6 mg/mL is recommended11. The serum voriconazole level could not be monitored in the presented patient because the test was not available at our hospital. According to the literature, voriconazole treatment is generally withdrawn when neurological and visual adverse effects develop, and symptoms were reported to disappear 24 hours–2 weeks after voriconazole cessation without any residue or sequel3,4,6,7. However, many patients must remain on the medication. It was reported that when the intravenous route of voriconazole administration is switched to the oral route due to the development of visual or neurological disturbances, such side effects generally disappear7. Continuation of oral voriconazole treatment is recommended in critical-condition patients7. In addition, there are reports of cases that developed neurological adverse reactions to voriconazole that improved spontaneously during ongoing treatment, as did the presented case3. In the presented patient, voriconazole could not be withdrawn or changed from the intravenous to the oral route because the patient had severe pulmonary aspergillosis and voriconazole treatment had been administered for only 4 days when the adverse effects developed; nonetheless, the symptoms resolved completely 4 days later. In conclusion, clinicians must be aware that voriconazole can cause visual disturbance and hallucinations. The differential diagnosis of visual disturbance is easier in cases accompanied by hallucination. Management of voriconazoleassociated visual and neurological toxicity includes discontinuation of the drug. Patients improve rapidly without sequelae after discontinuation of voriconazole, but cessation of treatment is not always necessary, as in some cases voriconazole-induced adverse effects resolve spontaneously while the treatment continues.
Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.
References 1. U.S. National Library of Medicine. http://livertox.nih.gov/ Narajo.html [last accessed 1 Feb 2015]. 2. Freifeld AG, Bow EJ, Sepkowitz KA, et al.; Infectious Diseases Society of America. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the infectious Diseases Society of America. Clin Infect Dis 2011;52:56–93. 3. Imhof A, Schaer DJ, Schanz U, Schwarz U. Neurological adverse events to voriconazole: evidence for therapeutic drug monitoring. Swiss Med Wkly 2006;136:739–742. 4. Eiden C, Peyrie`re H, Cociglio M, et al. Adverse effects of voriconazole: analysis of the French Pharmacovigilance Database. Ann Pharmacother 2007;41:755–763.
DOI: 10.3109/15569527.2015.1020544
Cutaneous and Ocular Toxicology Downloaded from informahealthcare.com by Kainan University on 04/06/15 For personal use only.
¨ sto¨r AJK. Hallucinations. In: Raftery AT, Lim 5. Raftery AT, Lim E, O ¨ sto¨r AJK, eds. Churchill’s pocketbook of differential diagnosis. E, O New York: Churchill Livingstone Elsevier; 2014:213–215. 6. Pasqualotto AC, Xavier MO, Andreolla HF, Linden R. Voriconazole therapeutic drug monitoring: focus on safety. Expert Opin Drug Saf 2010;9:125–137. 7. Zonios DI, Gea-Banacloche J, Childs R, Bennett JE. Hallucinations during voriconazole therapy. Clin Infect Dis 2008;47:e7–e10. 8. Zrenner E, Tomaszewski K, Hamlin J, et al. Effects of multiple doses of voriconazole on the vision of healthy volunteers: a doubleblind, placebo-controlled study. Ophthalmic Res 2014;52:43–52.
Voriconazole side effects
3
9. Imataki O, Ohnishi H, Kitanaka A, et al. Visual disturbance comorbid with hallucination caused by voriconazole in the Japanese population. Int J Hematol 2008;88:3–6. 10. Boyd AE, Modi S, Howard SJ, et al. Adverse reactions to voriconazole. Clin Infect Dis 2004;39:1241–1244. 11. Choi SH, Lee SY, Hwang JY, et al. Importance of voriconazole therapeutic drug monitoring in pediatric cancer patients with invasive aspergillosis. Pediatr Blood Cancer 2013;60:82–87. 12. Park WB, Kim NH, Kim KH, et al. The effect of therapeutic drug monitoring on safety and efficacy of voriconazole in invasive fungal infections: a randomized controlled trial. Clin Infect Dis 2012;55:1080–1087.
