Successful treatment of imported cerebral malaria with artesunate-mefloquine combination therapy.
ABSTRACT Treatment of cerebral malaria with intravenous quinine is frequently associated with life-threatening cardiotoxicity. We report a case of imported cerebral malaria successfully treated with artesunate-mefloquine combination therapy. The 27-year-old woman presented with fever, sudden onset of binocular blindness and altered consciousness 10 days after a short stay in Indonesia. Hyperparasitemia with Plasmodium falciparum and P. vivax in more than 5% of red blood cells was demonstrated on peripheral blood smear. She was admitted to the intensive care unit due to shock, jaundice and acute renal failure. Because of a shortage of intravenous quinine, intravenous artesunate was given as an alternative. Her condition stabilized on the 3rd day of therapy, with resolution of fever and disappearance of parasitemia. Consolidation therapy with oral mefloquine and primaquine was then given to prevent recrudescence and relapse. The only adverse event associated with artesunate was transient reticulocytopenia, which resolved after discontinuation of therapy. Her vision completely recovered, along with renal and liver function.
Article: Malaria eradication on islands.The Lancet 03/2001; 357(9255):560. · 38.28 Impact Factor
Article: Imported malaria: successful treatment of 31 patients in the era of chloroquine resistance.[show abstract] [hide abstract]
ABSTRACT: The diagnosis and management of imported malaria presents a continuing challenge in developed countries, including Taiwan. We retrospectively analyzed the records of all 31 patients with imported malaria treated at National Taiwan University Hospital from January 1984 through December 1998. Plasmodium falciparum was identified as the causative malarial parasite in 18 patients, P. vivax in 12, and P. ovale in one. All 31 patients had fever, but only 13 presented with the characteristic fever pattern. The most common initial laboratory abnormalities were thrombocytopenia (20/31), mild hyperbilirubinemia (20/31), and leukopenia (7/31). The median time from the onset of fever to the correct diagnosis was 4 days for P. falciparum and 5 days for P. vivax. In 28 cases, the clue that led to early diagnosis was the patient's travel history. Quinine, but not chloroquine, was effective in 17 out of 18 cases of falciparum malaria. Three patients treated with intravenous quinine required a change of regimen because of life-threatening quinine toxicity; artesunate served as a safe and effective alternative in this situation. While most patients with tertian malaria were cured with the standard chloroquine and primaquine regimen, a higher dosage was required for one case acquired in Papua New Guinea. All patients, including two with severe malaria, survived. We conclude that, the mortality of imported malaria in the chloroquine resistance era can be minimized with early recognition by obtaining a thorough travel history, and instituting appropriate antimalarial chemotherapy based on precise identification of species. Quinine toxicity should be closely monitoried, especially when this drug is given intravenously.Journal of the Formosan Medical Association 11/1999; 98(10):683-7. · 1.13 Impact Factor
[show abstract] [hide abstract]
ABSTRACT: Over 12 years, from 1984 to 1995, we conducted a prospective study of overall and malaria specific mortality among three rural populations in the Sahel, savanna and forest areas of Senegal. The emergence of chloroquine resistance has been associated with a dramatic increase in malaria mortality in each of the studied populations. After the emergence of chloroquine resistance, the risk of malaria death among children 0-9 years old in the three populations was multiplied by 2.1, 2.5 and 5.5, respectively. This is the first study to document malaria mortality at the community level in Africa before and after the emergence of chloroquine resistance. Findings suggest that the spread of chloroquine resistance has had a dramatic impact on the level of malaria mortality in most epidemiological contexts in tropical Africa.Comptes Rendus de l Académie des Sciences - Series III - Sciences de la Vie 09/1998; 321(8):689-97.
J Formos Med Assoc | 2006 • Vol 105 • No 1
H.Y. Sun, et al
Treatment of cerebral malaria with intravenous quinine is frequently associated with life-threatening
cardiotoxicity. We report a case of imported cerebral malaria successfully treated with artesunate-mefloquine
combination therapy. The 27-year-old woman presented with fever, sudden onset of binocular blindness
and altered consciousness 10 days after a short stay in Indonesia. Hyperparasitemia with Plasmodium falciparum
and P. vivax in more than 5% of red blood cells was demonstrated on peripheral blood smear. She was
admitted to the intensive care unit due to shock, jaundice and acute renal failure. Because of a shortage of
intravenous quinine, intravenous artesunate was given as an alternative. Her condition stabilized on the 3
day of therapy, with resolution of fever and disappearance of parasitemia. Consolidation therapy with oral
mefloquine and primaquine was then given to prevent recrudescence and relapse. The only adverse event
associated with artesunate was transient reticulocytopenia, which resolved after discontinuation of therapy.
Her vision completely recovered, along with renal and liver function. [J Formos Med Assoc 2006;105(1):86–
Key Words: artesunate, cerebral malaria, combination therapy, mefloquine
Department of Internal Medicine, National Taiwan University Hospital, Yun-Lin Branch, and National Taiwan University College of Medicine;
of Internal Medicine, National Taiwan University Hospital, Taipei, and National Taiwan University College of Medicine;
Pharmaceutical Science, National Taiwan University College of Medicine, Taipei, Taiwan, R.O.C.
2Graduate Institute of Clinical
Received: December 7, 2004
Revised: January 6, 2005
Accepted: April 12, 2005
Although endemic malaria was successfully
eradicated in 1965, there are still 40–50 cases of
imported malaria annually in Taiwan.1–5 With
the worldwide spread of chloroquine-resistant
Plasmodium falciparum since the late 1980s and
the consequent increased risk of malaria death,6,7
treatment of cerebral malaria presents a continu-
ing challenge. Intravenous quinine has been the
standard therapy for cerebral malaria caused
by chloroquine-resistant P. falciparum in Taiwan
since 1992. However, its use is frequently associ-
ated with life-threatening cardiotoxicity, including
pulmonary edema, myocardial suppression, hypo-
*Correspondence to: Dr. Shan-Chwen Chang, Department of Internal Medicine, National Taiwan University Hospital
and National Taiwan University College of Medicine, 7, Chung-Shan South Road, Taipei, Taiwan, R.O.C.
tension, and frank shock.5 Such toxicities may be
as hazardous as the disease itself. In contrast,
artemisinin-based combination therapy (ACT),
recommended by the World Health Organization
(WHO) as first-line treatment for malaria since
2001,8 is generally well tolerated and has many
advantages relating to the unique properties and
mode of action of the artemisinin component.9 The
use of ACT to treat severe malaria caused by chlo-
roquine-resistant P. falciparum remains extremely
limited in Taiwan. Here, we report a case of im-
ported cerebral malaria successfully treated with
artesunate-mefloquine combination therapy.
Successful Treatment of Imported Cerebral
Malaria with Artesunate-Mefloquine
Hsin-Yun Sun, Chi-Tai Fang,
1 Jann-Tay Wang,
1 Ping-Hung Kuo,
1 Yee-Chun Chen,
1 Shan-Chwen Chang
©2006 Elsevier & Formosan Medical Association
J Formos Med Assoc | 2006 • Vol 105 • No 1
Artesunate for cerebral malaria
loss of consciousness occurred soon after her
admission. Because of a shortage of intravenous
quinine, intravenous artesunate (120 mg immedi-
ately, followed by 60 mg 12 and 24 hours later,
and then once per day) was given as an alternative.
She was then transferred to the intensive care unit.
Initially, spiking fever persisted, and her conscious-
ness level and visual acuity continued to fluctuate.
Urine was black in color, and severe diarrhea was
also noted. Renal function (creatinine, 1.54 mg/
dL) deteriorated, and intravascular hemolysis,
black water fever with progression of anemia
(hemoglobin, 8.3 g/dL) and hemoglobinuria, and
hypotension (80/50 mmHg) also developed. Brain
magnetic resonance imaging revealed generalized
increased signal at the white matter of both hemi-
spheres on both T2 weighted and FLAIR images
compatible with encephalitis.
On the 3rd day of intravenous artesunate treat-
ment, parasitemia decreased to less than 0.1%.
Blood smear showed no parasitemia on the 4th day
and thereafter. The patient’s clinical condition and
laboratory abnormalities improved gradually un-
der appropriate management. However, worsen-
ing anemia (hemoglobin, 5.7 g/dL) and reticulo-
cytopenia (reticulocyte count, 0.27%) occurred on
the 4th day of intravenous artesunate therapy.
Artesunate-related reticulocytopenia was suspect-
ed, and artesunate was changed to oral meflo-
quine (750 mg-500 mg-250 mg every 8 hours) for
1 day as consolidation therapy followed by
oral primaquine (15 mg once daily) for eradica-
tion therapy. Her anemia and reticulocytopenia
improved after cessation of artesunate therapy.
However, severe anemia (hemoglobin, 3.5 g/dL)
developed again after 4 days of primaquine ad-
ministration. Primaquine-induced hemolytic ane-
mia due to glucose-6-phosphate dehydrogenase
(G6PD) deficiency was suspected. Although G6PD
level (19.41 U/g) was within normal limits, it
was difficult to interpret the significance of this
value soon after the episode of acute hemolysis.
Anemia improved after discontinuation of prima-
quine. She was discharged in good condition after
hospitalization for 20 days. Her vision completely
recovered, along with renal and liver function.
A 27-year-old Indonesian woman was admitted
to our emergency department because of sudden
onset of binocular blindness after a 2-day history
of fever, chills and intermittent vision loss. She
had been a domestic worker in Taipei for the past
2 years. Ten days before the onset of symptoms,
she had returned to Jakarta, Indonesia, and stayed
there for 8 days. She denied any raw food intake,
visiting places other than Jakarta, or mosquito bite
exposure during her stay in Indonesia. She had no
previous diagnosis of malaria, and her other past
medical history was unremarkable.
At the emergency department, the patient was
alert and oriented. Her pulse rate was 102 bpm,
blood pressure was 107/60 mmHg, respiratory rate
was 18/min, and body temperature was 36.1°C.
The conjunctiva was not pale, but the sclera was
icteric. The pupil sizes were equal, and light re-
flexes were preserved. Her facial expression was
symmetrical, and eye movement was full. No
sinus tenderness, nuchal rigidity or lymphadeno-
pathy was found. Examination revealed no abnor-
mality in the chest, heart or abdomen. The extrem-
ities were freely movable, and there was no rash,
purpura or petechiae. Visual acuity was hand wav-
ing at 10 cm. Ophthalmoscopic and neurologic
findings were normal.
Initial laboratory studies showed hemoglobin
12.4 g/dL, hematocrit 36.1%, leukocyte count
6920/µL, platelet count 140,000/µL, lactate de-
hydrogenase 1634 U/L, aspartate transaminase
73.0 U/L, total bilirubin 3.85 mg/dL, direct bi-
lirubin 2.8 mg/dL, blood urea nitrogen (BUN)
40.8 mg/dL, and creatinine 1.11 mg/dL. Urinaly-
sis was positive for protein, urobilinogen, bilirubin
and nitrite. Computed tomography of the head
without administration of contrast medium re-
vealed no hemorrhage or infarction but showed
mild brain swelling.
Because of her recent travel history, a blood
smear was performed to rule out malaria. Periph-
eral blood smears demonstrated ring form tropho-
zoites of P. falciparum and P. vivax in red blood
cells with hyperparasitemia over 5%. Sudden
J Formos Med Assoc | 2006 • Vol 105 • No 1
H.Y. Sun, et al
As in previously reported cases of imported
malaria, this patient presented with nonspecific
fever patterns, thrombocytopenia, and mild
hyperbilirubinemia.5 The diagnosis was made
promptly after obtaining a travel history and a
blood smear examination. Her condition was com-
plicated by cerebral malaria,10 evidenced by the
sudden onset of binocular blindness and altered
consciousness at admission, along with other in-
dicators of severe malaria including hyperparasi-
temia, shock, jaundice and acute renal failure.11
Nevertheless, prompt treatment with intravenous
artesunate led to a rapid clinical recovery without
the risk of life-threatening cardiotoxicity frequent-
ly associated with the use of intravenous quinine.
Intravenous artesunate can be a safe and effective
alternative to intravenous quinine for patients suf-
fering from life-threatening imported malaria in
Compared with quinine, artemisinin class com-
pounds have many advantages in falciparum ma-
laria treatment, such as rapid therapeutic response
(reduction of the parasite biomass and resolution
of symptoms), activity against multidrug-resistant
P. falciparum, good tolerance of the drug, and re-
duction in gametocyte carriage (and thus having
the potential to reduce transmission of malaria).12
However, when given as a single agent, recrudes-
cence rates are unacceptably high.13,14 Based on the
synergistic or additive potential of two drugs with
different mechanisms of action, in order to im-
prove therapeutic efficacy and to delay the emer-
gence of resistance to the artemisinin class of
compounds, the WHO endorses a policy of use
of ACT.8 The WHO has urged all countries experi-
encing resistance to conventional therapies, such
as chloroquine, amodiaquine or sulfadoxine/
pyrimethamine, to shift to one of the following
regimens: (1) artemether plus lumefantrine; (2)
artesunate plus amodiaquine; (3) artesunate plus
sulfadoxine/pyrimethamine (SP; in areas where SP
efficacy remains high); or (4) artesunate plus
mefloquine.8 In keeping with this policy, after the
completion of artesunate therapy in this patient,
we gave a full course of mefloquine as consolida-
tion treatment for P. falciparum infection. The treat-
ment for P. vivax coinfection, however, was not
completed because of the development of severe
hemolysis after 4 days of primaquine use.
Unlike quinine, artemisinin derivatives are
generally well tolerated by patients, although there
have been occasional reports of reticulocytopenia,15
manifested as worsening anemia after resolution
of fever, as experienced by our patient. Other re-
ported adverse effects included mild gastrointesti-
nal disturbance, dizziness, tinnitus and, rarely,
neutropenia, elevated liver enzyme values, prolon-
gation of the QT interval, bradycardia and
neurotoxicity.15–17 Although artemisinin derivatives
are generally safe, it would be prudent for clini-
cians to monitor the possible development of the
above-stated adverse drug effects during the thera-
In summary, compared to the cardiotoxic in-
travenous quinine regimen, artesunate-mefloquine
combination regimen can be considered as an ef-
fective and safe treatment alternative for patients
suffering from life-threatening imported malaria
in Taiwan, as demonstrated in this case.
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