□ CASE REPORT □

Akinetic Mutism Caused by HIV-associated Progressive
Multifocal Leukoencephalopathy was Successfully Treated
with Mefloquine: A Serial Multimodal MRI Study
Kasane Naito 1,2, Hiroki Ueno 1, Mayu Sekine 1,3, Munekazu Kanemitsu 1, Tomohiko Ohshita 1,4,
Takeshi Nakamura 1, Takemori Yamawaki 1 and Masayasu Matsumoto 1

Abstract
We report a case of a patient with highly active anti-retroviral therapy-resistant human immunodeficiency
virus (HIV)-associated progressive multifocal leukoencephalopathy (PML). The patient showed an improvement in imaging findings and clinical symptoms after mefloquine was introduced as an additional treatment.
Serial assessment of white matter lesions was conducted by proton magnetic resonance spectroscopy (1HMRS) and diffusion-weighted imaging (DWI). As the clinical symptoms improved, the N-acetylaspartate/creatine ratio increased, the choline/creatine ratio decreased, and the elevated ADC value decreased. These concomitant changes suggested that 1H-MRS and DWI were useful for the assessment of the therapeutic effect
on PML.
Key words: progressive multifocal leukoencephalopathy (PML), human immunodeficiency virus infection
(HIV), highly active anti-retroviral therapy (HAART), mefloquine, proton magnetic resonance
spectroscopy (1H-MRS), apparent diffusion coefficient (ADC)
(Intern Med 51: 205-209, 2012)
(DOI: 10.2169/internalmedicine.51.6253)

Introduction
Progressive multifocal leukoencephalopathy (PML) is a
demyelinating disease of the central nervous system caused
by JC virus (JCV). PML occurs among immunocompromised patients with leukemic disease, malignant lymphoma, human immunodeficiency virus (HIV) infection or
patients receiving immunosuppressive therapy. HIV-induced
immunodeficiency is the most common precipitating condition that leads to PML, and in an analysis of 9,675 cases of
PML in the US Nationwide Inpatient Sample database (1), it
was reported that HIV-associated PML (HIV-PML) accounted for 82% of all PML cases. Highly active antiretroviral therapy (HAART), which uses a combination of
more than three drugs, is a central component for the treatment of HIV and is effective for prolonging the life of pa-

tients. Obviously, the introduction of HAART is also effective for prolonging the life of HIV-PML patients (2). On the
other hand, the frequency of PML has not decreased as
compared to other opportunistic infections (3), and HAART
is not effective for about 50% of HIV-PML patients (2). In
2009, the anti-malarial drug mefloquine was revealed to
have anti-JCV activity in in vitro culture (4). Some cases in
which mefloquine has had an effect on PML have been reported (5, 6); however, there is no detailed report that mefloquine has an effect in HIV-PML. There have been many
reports of using diffusion-weighted imaging (DWI) and proton magnetic resonance spectroscopy (1H-MRS) for imaging
PML; however, there are only a few studies on white matter
lesions assessed by 1H-MRS during the therapeutic period.
We studied the serial changes of 1H-MRS and DWI in white
matter lesions of a patient with HAART-resistant HIV-PML
to whom mefloquine was introduced.

１

Department of Clinical Neuroscience and Therapeutics, Hiroshima University, Graduate School of Biomedical Sciences, Japan, ２Department of
Neurology, Hiroshima City Hospital, Japan, ３Department of Neurology, Tokyo Saiseikai Central Hospital, Japan and ４Department of Neurology,
Suiseikai Kajikawa Hospital, Japan
Received for publication July 25, 2011; Accepted for publication September 29, 2011
Correspondence to Dr. Hiroki Ueno, hirokiueno@hiroshima-u.ac.jp

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DOI: 10.2169/internalmedicine.51.6253

Figure 1. A, B and C show the initial MR study at admission (3 months after onset). A fluid attenuation inversion recovery (FLAIR) image showed hyperintense signals in the bilateral fronto-parietal white matter (A, B). A T1-weighted post-gadolinium contrast image showed no enhancement
(C). D, E and F show the follow-up MR study 8 months after onset (5 weeks after initiation of mefloquine). A FLAIR image showed progression of white matter abnormalities (D, E). A T1-weighted
post-gadolinium contrast image showed diffuse enhancement of white matter abnormalities (arrows)
(F).

Case Report
A 55-year-old man presented with memory impairment
and communication disorder in January 2010. His cognitive
dysfunction worsened, and he was admitted to our hospital
in mid-March. Clinical examination revealed attention disturbance, left hemispatial neglect, apraxia, memory impairment and dysarthria. The patient did not show any signs of
paralysis or involuntary movement, and muscle tonus and
tendon reflexes were normal. The white blood cell count
was 4.58×103/μL (CD4+ lymphocyte: 187/μL, CD8+ lymphocyte: 1,070/μL), HIV antibodies were positive, and HIV
RNA was 50.0×103 copies/mL in his blood. An examination
of the cerebrospinal fluid (CSF) showed increased protein
concentration (88 mg/dL) and a normal cell count (2/μL
with all mononuclear cells), and real-time polymerase chain
reaction (PCR) for JCV DNA in the CSF yielded positive
results, showing 535,500 copies/mL. On admission MRI
(Signa Excite HD 3.0 T: GE Medical Systems) showed T2
and fluid attenuated inversion recovery (FLAIR) asymmetrical high signals in the cerebral bilateral white matter, and
the cortex was almost completely intact although the lesion
involved the U-fibers. DWI (b-value, 1,000 s/mm2) showed
high signals in the part of hyperintense lesion on T2WI/

FLAIR. MR imaging did not show any gadolinium enhancement (Fig. 1A, B, C). MRS using the GE technique PROBE
with PRESS; TR 2,000 ms; TE 144 ms was performed, as
well. The 1H-MR spectrum was acquired from a localized
voxel of interest outlined in an axial FLAIR image of the
right frontal periventricular white matter lesion. The voxel
size was 20×20×20 mm (volume, 8 cm3). 1H-MRS showed a
substantially reduced N-acetylaspartate (NAA)/creatine (Cr)
ratio (NAA/Cr=0.57) and an elevated choline (Cho)/creatine
ratio (Cho/Cr=1.76) (Fig. 2A, B). On the apparent diffusion
coefficient map (ADC map), ADC values were measured in
five regions of interest in the right frontal periventricular
white matter lesion, and the values were found to increase
slightly (range 0.84 to 1.04, mean value 0.94×10-3 mm2/s)
(Fig. 2C, D). Probable PML associated with HIV infection
was diagnosed.
HAART was initiated in April 2010, four months after the
onset of symptoms. Following treatment, the HIV-RNA level
decreased, but CD4+ lymphocytes were under 200/μL
throughout the course and did not show substantial elevation. The MRI findings and clinical manifestations deteriorated, and the patient developed left flaccid hemiplegia and
experienced akinetic mutism. In June 2010, about six
months after the onset, treatment with mefloquine hydrochloride tablets was started at 275 mg/day orally for three

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DOI: 10.2169/internalmedicine.51.6253

Figure 2. 1H-MRS and DWI were performed on March 26, July 29 and August 11. A. 1H-MR
spectrum acquired from a localized voxel of interest outlined on an axial FLAIR image of the right
frontal periventricular white matter lesion. B. Serial change of 1H-MRS at three time points. The
third 1H-MRS (5 weeks after the initiation of mefloquine) showed an increased ratio of N-acetylaspartate (NAA) and a decreased ratio of choline (Cho) to creatine (Cr) with improvement of symptoms. C. The ADC value was measured in the apparent diffusion coefficient map (ADC map) in five
regions of interest (i.e., 1-5) in the right frontal periventricular white matter lesion. D. Serial changes
of the ADC value at three time points. ADC values showed a slight upward tendency, whereas some
ADC values (i.e. 1,4,5) decreased at the third DWI study.

days and was then continued at 275 mg once a week. This
course followed the administration protocol of Kishida et
al (7) as a modification of the Biogen Idec mefloquine treatment protocol taken from the clinicaltrials.gov website (8).
According to the instructions of the ethical review board at
Hiroshima University Hospital, informed consent regarding
the use of mefloquine was obtained from the patient’s family prior to introduction of the therapy. About eight months
after the onset, and five weeks after mefloquine was started,
the patient showed some improvement of clinical symptoms,
and an MRI revealed enhancing white matter lesions
(Fig. 1D, E, F). 1H-MRS of the right frontal lesion showed a
further reduction in NAA (NAA/Cr=0.38) and elevated Cho
(Cho/Cr=1.97) (Fig. 2B). All ADC values showed an increasing trend, and the mean ADC value was 1.244×10-3
mm2/s (range 1.12 to 1.40×10-3 mm2/s) (Fig. 2D). The patient’s clinical condition continued to improve, and he began
to let out a single tone and showed improved muscle
strength in his left arm and leg. 1H-MRS performed seven
weeks after mefloquine was introduced showed recoveries of
reduced NAA (NAA/Cr=0.63) and elevated Cho (Cho/Cr=
1.56) in comparison to the levels at admission (Fig. 2B).
Several ADC values showed a slight decreasing trend, and

the mean ADC value was 1.164×10-3 mm2/s (range 1.10 to
1.31×10-3 mm2/s) (Fig. 2D). Eight weeks after mefloquine
was introduced, CSF PCR findings for JCV were negative.
In August 2010, the patient was transferred to another hospital.

Discussion
Compared with the era before combined anti-retroviral
therapy, the incidence and mortality of HIV-PML are currently reduced; however, HIV-PML is still a fatal disease
due to the treatment-resistant cases. Several factors are considered to be involved in HIV-PML prognosis including
CD4+ T cell count. Marzocchetti et al (9) reported that the
estimated 1-year survival rate was 48% in HIV-positive
PML patients with a CD4 count <200/μL at PML diagnosis
compared to 67% in those with a CD4 count >200/μL. In
addition, JC viral load in the CSF can be attributed to longterm survival. In a study of 61 HIV-infected patients with
PML, Bossolasco et al (10) reported that JCV DNA levels
of >3.64 log copies/mL were significantly correlated with a
shorter survival. And thus the reasons for the resistance to
HAART in the present case may include low-CD4+ T cell

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counts and high levels of JCV DNA during therapeutic period.
Recently, the anti-malarial drug mefloquine, which is considered to have anti-JCV action, is expected to have an effect on PML, and a randomized study is currently underway (8). Gofton et al (5) reported a patient with sarcoidosis
who was treated with 1,000 mg/week mefloquine that was
initiated six months after symptom onset. Clinical progression stopped immediately, and the JC virus then became undetectable in the CSF. Kishida and Tanaka (6) reported a patient after an umbilical cord blood transplant that showed favourable clinical, neuroradiological and virological responses after the initiation of mefloquine. To our knowledge, the present case is the first detailed report that demonstrates that mefloquine combined with HARRT gave a positive outcome to a patient with HIV-PML. Although mefloquine was initiated six months after symptom onset, the result implies that mefloquine has the ability to improve
symptoms of HAART-resistant PML even in the chronic
phase.
Image findings in PML reflect demyelination and provide
helpful information for diagnosis. Contrast enhancement is
usually absent in classic PML lesions on MRI because the
lesions are oligodendrocyte cell death caused by persistent
JCV infection, which indicates that the lesions are not associated with inflammation. It is possible that contrast enhancement in PML is caused by mechanisms of the inflammatory response induced when JCV is eliminated by the immune system. When this response causes massive cellular
destruction after initiation of HAART, an HIV-PML patient’s clinical condition sometimes becomes worse. This
worsening is known as immune reconstitution inflammatory
syndrome. However, once JCV is eliminated by the immune
system, an improvement in the prognosis can be expected.
There are reports that contrast enhancement is a favourable
treatment response (11, 12) and associated with a longer
survival (13-15). In the present case, the PML was advanced, because the CD4+ T cell count did not increase, and
the immune system did not recover only by HAART. About
five weeks after mefloquine was initiated, an MRI showed
an enhancing lesion corresponding to symptomatic improvement. This MRI finding may imply an inflammatory response against JCV-infected cells in the lesion.
There have been some studies on white matter lesions using DWI. It has been shown that the ADC value in a recent
lesion and an advancing edge of established lesion decreases, and the ADC value in an old lesion and in the center of the lesion increases (16-18). In the present case, as the
clinical condition became worse, the elevated ADC value in
the lesion showed a further increase in spite of HAART. In
PML lesions, an increased ADC value indicates pathologically enlarged extracellular space and a loss of myelin (17).
There are some reports of serial ADC value changes in PML
patients treated with HAART (18, 19). Usiskin et al (18) reported an HIV-PML patient who presented a decreased ADC
value with a favourable response to therapy, and they sug-

gested that the change implied microstructural reorganization. In the present case, the ADC value also decreased
slightly with an improvement in the clinical condition after
the introduction of mefloquine. There is a possibility that facilitated diffusion becoming slightly more restricted shows
remyelination in the white matter lesion.
Early 1H-MRS studies of patients with PML have revealed that decreased NAA concentrations [which indicate
neuronal damage (20)], elevated Cho (which indicates demyelination), and the appearance of a lactate peak (which
indicates impaired energy metabolism) (21-23). In the present case, serial changes of 1H-MRS were observed. 1HMRS performed seven weeks after mefloquine was introduced revealed elevated NAA/Cr and reduced Cho/Cr, reflecting an improvement in clinical symptoms. This change
may indicate a functional improvement of infected oligodendrocytes by anti-JCV effects of mefloquine. Several studies
have demonstrated that a decrease of NAA could be partially reversible in acute demyelinating lesions (such as
those that occur in multiple sclerosis patients) (24-26).
There is a possibility that mefloquine is effective in the
chronic phase of HAART-resistant cases of HIV-PML. The
present results suggest that, in addition to contrast enhancement, DWI and 1H-MRS may offer valuable information on
the microstructural reorganization process that occurs after
mefloquine inhibits oligodendrocyte death.
The authors state that they have no Conflict of Interest (COI).
Acknowledgement
The authors are grateful to Dr. Kazuo Nakamichi and Dr.
Masayuki Saijo (Department of Virology 1, National Institute of
Infectious Diseases) for determinations of JCV in CSF and Dr.
Motohiro Yukitake (Division of Neurology, Department of Internal Medicine Faculty of Medicine, Saga University) for helpful
suggestions on the use of mefloquine.

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