Download letters to the editor a case-control auditory evaluation of patients

Am. J. Trop. Med. Hyg., 74(6), 2006, pp. 939–940
Copyright © 2006 by The American Society of Tropical Medicine and Hygiene
LETTERS TO THE EDITOR
A CASE-CONTROL AUDITORY EVALUATION OF PATIENTS TREATED WITH
ARTEMETHER-LUMEFANTRINE
die than other artesunate recipients; patients treated with quinine who developed late hypoglycemia were not more likely
to die than other quinine recipients. This finding is fully compatible with the known mechanism of artemisinin neurotoxicity: severe neuronal energy depletion with collapse of the
inner mitochondrial membrane potential and profound ATP
depletion in brainstem neurons. Energy-depleted neurons
might be hard pressed to survive the additional challenge of
hypoglycemia.
Inconvenient as it might be, evidence that currently deployed artemisinins might well be neurotoxic is accumulating14 and needs to be confronted. Given the enthusiasm for,
and widespread deployment of, these agents, a careful and
thoughtful re-examination of artemisinin neurotoxicity is
called for, with studies that are capable of making a meaningful contribution.
Dear Sir,
There are now three reports of human ototoxicity with artemisinin or artemisinin combination treatments (ACTs; Adjei and others, unpublished data).1–3 All of these studies conducted baseline audiograms before drug exposure and were
able to measure hearing threshold shifts in individual subjects
and to detect subtle losses in hearing threshold.
One of the studies that conducted baseline audiometry was
performed in healthy volunteers.1 An ototoxicity study in subjects with severe malaria, which included baseline audiograms,
showed fully reversible shifts in hearing threshold under treatment with quinine.4,5 These facts all point away from malaria
and toward artemisinins and ACTs as a cause of hearing loss.
A recently published Thai study had hoped to provide reassurance that artemether-lumefantrine was not ototoxic.6
Given the deficiencies of this Thai study, it is unable to offer
such reassurance.
First, the Thai study failed to include any baseline measurements (i.e., pre-drug exposure measurements). This fundamental weakness precludes the Thai study from drawing
any conclusions about hearing threshold shifts in individual
subjects. This same deficiency was also present in two earlier
studies quoted by the Thai report.7,8 The need for baseline
audiometry was pointed out in the original Mozambican paper referred to by the Thai paper, as well as in subsequent
published correspondence. 2,9,10 The two earlier studies
quoted in the Thai report also suffered from lack of drug
exposure standardization.7,8
Second, the degree of hearing loss reported in both treated
subjects and controls in the Thai study is a major confounder.
Given the magnitude of the threshold shifts reported in both
treated subjects and controls, it is quite possible that any subtle
artemether-lumefantrine associated threshold shift would
have been obscured and consequently remained undetected.
Third, the long interval between drug exposure and audiometry in the Thai study lays it open to any number of additional confounders. In contrast, all subjects in the Mozambican study lived and worked in the same environment and
had post-exposure audiometry conducted before discharge
from that environment.
With regard to the necropsy study quoted in the Thai report,11 Schmuck and others12 have shown that artemisinininduced neurotoxicity does not manifest microscopically before day 7 after exposure, with the total extent of cell injury
or death not fully manifest before day 14 after exposure. This
crucial, but apparently overlooked, finding must cast doubt
on the necropsy study, in which the median time between
initiation of artemisinin therapy and death was 76.5 hours
(interquartile range, 8–331 hours); the findings of Schmuck
and others also call into question a large number of animal
artemisinin safety studies.
Recently emerged additional data from the SEAQUAMAT study also support clinical artemisinin neurotoxicity.13
In this study, malaria patients treated with intravenous artesunate who developed late hypoglycemia were more likely to
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LETTERS TO THE EDITOR
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14. Franco-Paredes C, Dismukes R, Nicolls D, Kozarsky PE, 2005.
Reply to Newton et al. Clin Infect Dis 41: 1688–1689.
STEPHEN TOOVEY
Royal Free and University College Medical School
London, United Kingdom