Introduction
Mucosal leishmaniasis is a form of American tegumentary leishmaniasis caused by the parasite Leishmania (Viannia) braziliensis.Reference Goodwin1, Reference Di Lella, Vicenti, Zennaro, Afeltra, Baldi and Giordano2 In many cases, mucosal leishmaniasis results from the vascular dissemination of L (Viannia) braziliensis from skin lesions.Reference Amato, Tuon, Bacha, Neto and Nicodemo3
Although therapeutic practice varies from country to country, leishmaniasis has been preferentially treated with antimonials for more than 60 years.Reference Goodwin1, Reference Vianna4 The two main therapeutic agents, meglumine antimoniate and sodium stibogluconate, differ in terms of dosage, treatment duration and administration frequency (continuous or intermittent).Reference Berman5–9 At the Laboratory of Leishmaniasis Surveillance, Evandro Chagas Clinical Research Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil, we have found continuous or intermittent intramuscular administration of meglumine antimoniate at a dose of 5 mg/kg/day to be effective and well tolerated.Reference Oliveira-Neto, Schubach, Araujo and Pirmez10–Reference Schubach, Marzochi, Moreira, Schubach, Araújo and Francesconi-do-Vale15
The main side effects of treatment with pentavalent antimonials are myalgia, arthralgia, electrocardiographic Q–T interval prolongation, renal failure and pancreatitis accompanied by elevated lipase levels, among others.Reference Azeredo-Coutinho and Mendonca7, Reference Oliveira-Neto, Schubach, Mattos, Goncalves-Costa and Pirmez11, Reference Oliveira-Neto, Mattos, Pirmez, Fernandes, Goncalves-Costa and Souza13, Reference Cuce, Belda and Dias16, Reference Gasser, Magill, Oster, Franke, Grogl and Berman17 Older individuals are more affected by mucosal leishmaniasis and also more prone to the side effects of treatment,Reference Oliveira-Neto, Mattos, Pirmez, Fernandes, Goncalves-Costa and Souza13 in addition to presenting other risk factors for the occurrence of dizziness. In recent years, our group has occasionally observed dizziness in elderly patients, related to the use of meglumine antimoniate. Dizziness has been reported as an adverse effect of meglumine antimoniate used to treat American tegumentary leishmaniasis.Reference Passos, Barreto, Romanha, Krettli, Volpini and Gontijo18 However, there are no published data describing possible risk factors associated with episodes of dizziness occurring during pentavalent antimonial treatment for mucosal leishmaniasis.
The term dizziness is used to describe a sensation of unsteadiness that manifests as instability, oscillation, fluctuation and deviation of gait, disequilibrium, fainting, short episodes of mental confusion, loss of consciousness, spatial disorientation, and epileptiform episodes. Dizziness should be distinguished from vertigo, which refers to the perceived movement of one's own body or of the environment, and is sometimes accompanied by nausea.Reference Araújo19, Reference Grimby and Rosenhall20 The risk factors associated with dizziness include cardiovascular, cerebrovascular, neurological, sensory, osteoarticular, psychological and gastrointestinal diseases, as well as diabetes.Reference Oliveira-Neto, Mattos, Pirmez, Fernandes, Goncalves-Costa and Souza13, Reference Grimby and Rosenhall20–Reference Katsarkas29
In Brazil, dizziness has attracted little public health interest, and its association with medication usage has not been well studied.28 International studies suggest that a complete patient history and physical examination are more important for the diagnosis of dizziness than are complementary examinations.Reference Colledge, Barr-Hamilton, Lewis, Sellar and Wilson23, Reference Davis30, Reference Lawson, Fitzgerald, Birchall, Aldren and Kenny31 Studies also suggest that predisposing factors may not have such a specific relationship with the aetiological diagnosis as has previously been thought.Reference Tinetti, Williams and Gill25, Reference Kao, Nanda, Williams and Tinetti27, Reference Katsarkas29, Reference Piker, Jacobson and McCaslin32
The aim of the current study was to determine the factors associated with the occurrence of dizziness in patients with mucosal leishmaniasis treated with meglumine antimoniate.
Materials and methods
We conducted a descriptive, retrospective study which reviewed the medical records of patients with mucosal leishmaniasis who had been treated with meglumine antimoniate at the Laboratory of Leishmaniasis Surveillance, Evandro Chagas Clinical Research Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil, between 1 January 1989 and 31 December 2004.
The criteria for the diagnosis of mucosal leishmaniasis were: a compatible epidemiological history; suggestive mucosal lesions as seen on video-nasopharyngolaryngoscopy; a positive Montenegro skin test and/or visualisation of the parasite on histopathological examination, imprint or culture; and (eventually) positive serology by indirect immunofluorescence or enzyme immunoassay.
Patients with other forms of American tegumentary leishmaniasis and those treated with drugs other than meglumine antimoniate were excluded.
Patients were treated with either (1) an intramuscular dose of 5 mg meglumine antimoniate/kg/day until epithelialisation of the lesion, no more than 120 doses, or (2) an intramuscular dose of ≤10 mg meglumine antimoniate/kg/day for 30 days. In both dosage groups, patients received the medication either continuously, or in an intermittent regime of 10 days with medication followed by 10 days without medication.
Clinical and laboratory examinations were conducted before, during, on completion and one month after completion of treatment to monitor toxicity. These included routine serum biochemical analyses (investigating serum glucose, alkaline phosphatase, alanine aminotransferase (ALT), aspartate aminotransferase (AST) urea, creatinine, amylase and lipase), haematological examinations and electrocardiography.
Dizziness was considered as an adverse effect only if it appeared during treatment or up to one month after treatment completion. No specific tests, such as vestibular function tests, were available during the study period.
The analysed variables were selected because of their possible relevance to the onset and progression of dizziness in the group investigated (Tables I and II). The severity of clinical, biochemical, haematological and electrocardiographic side effects was classified according to an adapted version of the 1992 acquired immunodeficiency syndrome table for grading the severity of adult adverse experiences, in which G1 = mild side effect, G2 = moderate side effect, G3 = severe side effect and G4 = life-threatening side effect.33
Characteristics of continuous patient variables, by presence or absence of dizziness
Data represent means ± standard deviations unless otherwise specified. *Significant at 20 per cent level. Y = years; MA = meglumine antimoniate
Distribution of patient variables* by presence or absence of dizziness
* Monitored before, during and ≥30 days after completion of meglumine antimoniate (MA) treatment. †n = 121; ‡n = 6. **Significant at 20 per cent level. OR = odds ratio; CV = cardiovascular; ↑= raised; AST = aspartate transaminase; ALT = alanine transaminase; ECG = electrocardiograph
Categorical variables (i.e. gender, treatment type and occurrence of adverse events) were reported as simple frequencies. Measures of central tendency and dispersion were used for discrete or continuous quantitative variables (i.e. age, duration of treatment and total dose). The strength of the association between dizziness and the covariables of interest was evaluated using odds ratios and 80 per cent confidence intervals. Significant differences between the proportions were determined using Fisher's exact test, and the differences between the means of continuous variables were evaluated using Student's t-test. Variables were selected according to their theoretical relevance or statistical significance (considered at p < 0.20), and were analysed by a stepwise (backward elimination using Wald's test), non-conditional logistic regression. The entry criterion was set at 0.10 (p < 0.10) and the retention criterion at 0.15 (p > 0.15), for the Wald statistical test. The Hosmer–Lemeshow test showed no lack of fit (p > 0.05). The data were processed and analysed using the Statistical Package for the Social Sciences software package (version 11.0).
The project was approved by the ethics committee on research involving humans of the Evandro Chagas Clinical Research Institute, Oswaldo Cruz Foundation.
Results and analysis
We studied a total of 127 patients (31.4 per cent females, 68.6 per cent males) ranging in age from four to 90 years (mean ± standard deviation (SD), 50.9 ± 19.4 years). Of these patients, 110 (86.6 per cent) were treated with 5 mg meglumine antimoniate/kg/day and 17 (13.4 per cent) with ≥10 mg meglumine antimoniate/kg/day. The continuous and intermittent regimens were used in 71.8 and 28.2 per cent of patients receiving 5 mg meglumine antimoniate/kg/day, respectively, and in 82.35 and 17.64 per cent of patients receiving ≥10 mg meglumine antimoniate/kg/day, respectively. The duration of treatment ranged from 4 to 133 days (mean ± SD, 47.4 ± 26.7 days), with 115 (90.5 per cent) patients completing treatment. Twelve (9.5 per cent) patients did not complete treatment: six due to drop-out, five due to the presence of side effects, and one due to other, non-specified reasons. Therapeutic success was obtained in 102 (88.6 per cent) of the 115 patients who completed the treatment.
Dizziness was reported by 4.7 per cent of the 127 patients. When comparing the means of continuous variables, only patient age showed a statistically significant association with dizziness (p < 0.086) (Table I).
A bivariate analysis at a level of significance of 20 per cent showed significant associations between dizziness and female gender, patient age of 60 years or older, elevated serum lipase and the presence of cardiovascular alterations (Table II). The other variables cited in Table II were included in the logistic regression model due to their theoretical relevance.
Table III shows the crude and logistic regression adjusted odds ratios for the occurrence of dizziness in the presence of various categorical variables, together with 90 per cent confidence intervals. These results show that only female gender, age of 60 years or older and elevated serum lipase remained significant.
Crude and adjusted* odds ratios and confidence intervals for occurrence of dizziness in the presence of various categorical variables
* By logistic regression.
†Significant at 10 per cent level. Cr = crude; OR = odds ratio; adj = adjusted; CI = confidence interval; y = years
Discussion
Although leishmaniasis is an important endemic disease and a public health issue in underdeveloped countries, the increase in developing world tourism has resulted in the extension of this problem to developed countries.Reference Tuon and Amato34
As our study was retrospective, the validity of our data could be questioned due to the lack of objective testing of outcome measures (e.g. by vestibular tests) and the lack of detailed history-taking regarding the nature of the dizziness. Dizziness is a subjective symptom which represents different and overlapping sensations, and which may be caused by different pathophysiological mechanisms representing several differing diagnoses.
On the other hand, the strong points of our study included regular patient follow up, and systematic investigation of side effects by clinical, biochemical, haematological and electrocardiographic examination, thus permitting evaluation of a large number of variables.
Ototoxicity is a relatively rare cause of disequilibrium which is related to the use of chemical substances. There are a wide variety of ototoxic drugs (at least 130), the most commonly used being aminoglycoside antibiotics, salicylates, quinine, antineoplastic agents and loop diuretics. Risk factors associated with ototoxicity include an elevated concentration of the drug in serum or in the inner ear, hypoalbuminaemia, renal function impairment, previous inner ear damage, previous or concomitant treatment with another ototoxic medication, fever, dehydration, bacteraemia, hereditary factors, female gender, noise exposure, and advanced age.Reference Seligmann, Podoshin, Ben-Davis, Fradis and Goldsher35 In the present study, a higher risk of dizziness was observed among females, elderly individuals and those with elevated serum lipase.
We found no association between dizziness and treatment duration, a drug dose of ≥10 mg meglumine antimoniate, or receiving a greater number of meglumine antimoniate doses. This is probably because most patients received the low-dose regimen (5 mg meglumine antimoniate/kg/day) usually used in our service.
The most common cardiovascular side effects associated with the use of meglumine antimoniate are electrocardiographic Q–T interval prolongation and arrhythmias.Reference Azeredo-Coutinho and Mendonca7, Reference Oliveira-Neto, Schubach, Mattos, Goncalves-Costa and Pirmez11, Reference Oliveira-Neto, Schubach, Mattos, Goncalves-Costa and Pirmez12 However, no significant association has been observed between dizziness and alterations in cardiac rhythm.Reference Ensrud, Nevitt, Yunis, Hulley, Grimm and Cummings21 Similarly, in the present study multivariate logistic regression analysis revealed no association between dizziness and cardiovascular side effects.
The association between dizziness and diabetes is controversial, and has been reported by some investigatorsReference Grimby and Rosenhall20, Reference Ensrud, Nevitt, Yunis, Hulley, Grimm and Cummings21, Reference Kao, Nanda, Williams and Tinetti27 but not others.Reference Colledge, Wilson, Macintyre and MacLennan22–Reference Tinetti, Williams and Gill24, Reference Hillen, Wagner and Sage36 We found no association between hyperglycaemia and dizziness.
• Meglumine antimoniate is used to treat mucosal leishmaniasis
• Dizziness may be an adverse effect of this drug, especially in females, elderly individuals and those with elevated serum lipase
• If meglumine antimoniate treatment is not interrupted, permanent vestibular damage may occur
The data reported here suggest that there is no association between dizziness and altered renal function (as detected by conventional laboratory analysis). This conclusion is in contrast with published literature which suggests that nephrotoxic drugs may be potentially ototoxic, whereas the use of substances with a known nephroprotective action may be potentially otoprotective.Reference Walker, Fazekas-May and Bowen37–Reference Hyppolito, Oliveira, Lessa and Rossato39 Analysis of other biochemical parameters indicated no association between dizziness and hypercholesterolaemia or hepatic alterations; this is in agreement with the literature.Reference Araújo19, Reference Davis30, Reference Cohen40
Previous studies have reported an association between gastrointestinal medication usage and dizziness,Reference Dukes and Aronson41 as well as between gastrointestinal disease and dizziness.28 Our findings agree with these reports, and show that elevated serum lipase levels, indicating pancreatic toxicity related to the use of meglumine antimoniate, are an important risk factor for the development of dizziness among patients taking this drug.
Conclusions
These study findings indicate that dizziness may occur as an adverse effect related to the use of meglumine antimoniate, especially in females, elderly individuals and those with elevated serum lipase. If meglumine antimoniate treatment is not interrupted, permanent vestibular damage may occur.
As a result of these observations, we are conducting additional studies with complete cochleo-vestibular evaluation, to better investigate meglumine antimoniate related ototoxicity.
