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Mefloquine improved progressive multifocal leukoencephalopathy in a patient with immunoglobulin A nephropathy
Journal of Clinical Neuroscience xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Review
Mefloquine improved progressive multifocal leukoencephalopathy in a patient with immunoglobulin A nephropathy Jung-Won Shin a, Keun-Hwa Jung a, Soon-Tae Lee a, Jangsup Moon a, Jung-Ah Lim a, Jung-Ick Byun a, Kyung-Il Park b, Sang Kun Lee a, Kon Chu a,⇑ a b
Department of Neurology, Seoul National University Hospital, 101 Daehang-no, Chongro-gu, Seoul 110-744, South Korea Department of Neurology, Seoul Paik Hospital, Inje University College of Medicine, Seoul, South Korea
a r t i c l e
i n f o
Article history: Received 7 August 2013 Accepted 19 December 2013 Available online xxxx Keywords: IgA nephropathy Mefloquine Progressive multifocal leukoencephalopathy
a b s t r a c t We describe a patient with immunoglobulin A nephropathy who was diagnosed with progressive multifocal leukoencephalopathy (PML) and successfully treated with mefloquine, an antimalarial medication. A 67-year-old man with immunoglobulin A nephropathy presented to the hospital emergency room with fever and generalized tonic-clonic seizure. Cerebrospinal fluid (CSF) nested polymerase chain reaction (PCR) was positive for John Cunningham virus and brain MRI displayed high signal intensity in the white matter in the right parietal lobe without gadolinium enhancement. Tapering of prednisone did not arrest the disease progression and a new lesion was detected on the cerebellum. Administration of mefloquine stopped lesion progression and resulted in dramatic clinical improvement. The CSF nested PCR for the John Cunningham virus also became negative. In reviewing the literature, mefloquine has had a heterogeneous effect in PML patients, and P-glycoprotein polymorphism and proper dosage could contribute to the various effects seen. Mefloquine may be a favorable treatment option in some patients with PML, and P-glycoprotein polymorphism may play an important role in its efficacy. More large studies in other ethnic groups including polymorphism studies for the gene encoding P-glycoprotein (ABCB1/MDR1) and taking into account various underlying conditions with secondary immunosuppression should be carried out to investigate whether mefloquine is effective for treating PML. Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
2. Case report
Progressive multifocal leukoencephalopathy (PML) presents clinically as a focal or multifocal neurologic disorder, and the disease was named for the neuropathological observation of microscopic multifocal lesions involving the white matter of the brain [1]. PML is caused by John Cunningham (JC) virus infection of the oligodendrocytes in the white matter of the brain, which leads to neurologic deficits. JC virus-induced PML is regarded as an opportunistic infection of the human nervous system [2]. Although there is no treatment proven to be effective for PML, mefloquine, a widely used antimalarial agent, has been recently reported to inhibit the JC virus infection in vitro and produce some clinical improvement. We report the beneficial effect of mefloquine in a Korean patient with PML associated with immunoglobulin (Ig) A nephropathy.
A 67-year-old right-handed man with IgA nephropathy and type 2 diabetes mellitus visited the hospital emergency room with fever and seizure. He was diagnosed with IgA nephropathy in 2004. Due to recent disease progression, he had commenced prednisone 25 mg daily in January 2013. Three months later, he presented with fever and one episode of a generalized tonic-clonic seizure. On hospital day 1, he had no neurological deficit and laboratory tests showed mild leukocytosis and elevated blood urea nitrogen (59 mg/dL, normal range: 7–20 mg/dL) and creatinine (3.56 mg/dL, normal range: 0.8–1.4 mg/dL). Brain MRI (diffusion weighted, T2weighted and fluid attenuated inversion recovery [FLAIR] imaging) displayed high intensity signal of the white matter in the right parietal lobe without gadolinium enhancement (Fig. 1). A lumbar puncture was performed and cerebrospinal fluid (CSF) analysis showed mild pleocytosis (white blood cells 82 cells/mm3, normal range: 0–3 cells/mm3, lymphocyte 57%, others 25%) with slightly elevated protein concentration (94 mg/dL, normal range: 40–85 mg/dL). Cryptococcus antigen and bacterial staining were
⇑ Corresponding author. Tel.: +82 2 2072 1878; fax: +82 2 3672 4949. E-mail address: [email protected] (K. Chu). http://dx.doi.org/10.1016/j.jocn.2013.12.031 0967-5868/Ó 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Shin J-W et al. Mefloquine improved progressive multifocal leukoencephalopathy in a patient with immunoglobulin A nephropathy. J Clin Neurosci (2014), http://dx.doi.org/10.1016/j.jocn.2013.12.031
2
J.-W. Shin et al. / Journal of Clinical Neuroscience xxx (2014) xxx–xxx
A
C
B
D
Fig. 1. Fluid attenuated inversion recovery axial MRI on presentation (A), on hospital day 9 (B) and follow-up images 2 months later (C, D). After disease progression, a new lesion developed in the bilateral cerebellum without enhancement (B) and after treatment at 2 months later, the right parietal lesion decreased and the cerebellar lesion disappeared (C, D).
negative. Generalized delta to theta activity was seen on electroencephalography. We immediately started valacyclovir 1000 mg twice a day and oxcarbazepine 450 mg twice a day. After 1 week, CSF polymerase chain reaction (PCR) tests showed negative results for herpes simplex, varicella zoster, cytomegalovirus, Epstein-Barr virus, mycobacterium, Legionella pneumophila, Mycoplasma pneumonia and BK virus. However JC virus PCR was positive, so prednisone was tapered to 7.5 mg daily. On hospital day 9, he complained of dizziness, nausea and gait disturbance. Ataxia was present in the left upper extremity on neurological examination and he showed gaze evoked nystagmus. In a follow-up brain MRI, the previous lesions had extended and a new high signal intensity lesion in the bilateral cerebellum developed on FLAIR imaging (Fig. 1). We tapered prednisone but his symptoms progressed. Therefore, on hospital day 14, we commenced mefloquine as it had been an effective therapy for PML in previous case reports. After 275 mg of mefloquine for 3 days, on hospital day 16, his symptoms stabilized and gradually improved. In a follow-up CSF examination, JC virus PCR was not detected. We continued mefloquine 275 mg once a week for 2 months and he developed no more neurological deficits and smaller brain lesions on follow-up imaging (Fig. 1).
3. Discussion JC virus-induced damage of oligodendrocytes leads to focal myelin loss and this manifests as dysfunction of the cerebral hemispheres, cerebellum or brainstem [2]. Although human immunodeficiency virus (HIV) infection remains the most common predisposing factor for PML, it can also occur as a complication of other chronic illness associated with secondary immunosuppression. As IgA nephropathy is characterized by deposition of the IgA antibody in the glomerulus, steroids and cyclophosphamide are used to preserve renal function in the high risk population. This is the first PML patient with IgA nephropathy treated by steroids to our knowledge. Berger et al. established criteria for the diagnosis of PML and recommended a diagnostic algorithm. In the algorithm, the presence of classic radiographic findings and clinical features consistent with the diagnosis coupled with a positive CSF JC virus PCR is sufficient for unequivocal diagnosis of PML [3]. Our patient satisfied these three factors. No treatments have proven to be effective for PML. The general principle of treatment is to improve the immune status. Studies have investigated drug therapy using cytosine arabinoside, cidofovir, mirtazapine, risperidone and mefloquine. Among the
Please cite this article in press as: Shin J-W et al. Mefloquine improved progressive multifocal leukoencephalopathy in a patient with immunoglobulin A nephropathy. J Clin Neurosci (2014), http://dx.doi.org/10.1016/j.jocn.2013.12.031
Patient age, sex, nationality
Initial symptoms
Comorbidity
Treatment of comorbidity
Mefloquine
Treatment response
Brain MRI
CSF analysis
Histology
Reference
55, M, Japanese
Akinetic mutism
HIV/AIDS
HAART
275 mg/day for 3 days, followed by 275 mg once a week
Yes
R frontal subcortical lesion
No biopsy
Naito [13]
60, M, Japanese
Parkinsonism
Sarcoidosis
None
Yes
Limb weakness
SLE
JC virus: negative
Done
Hirayama [14] Beppu [9]
37, M, Japanese
Psychomotor slowing, aphasia, limb weakness
AML
Prednisone 20 mg daily Ara-C/ Prednisolone
R frontal subcortical lesion R frontal subcortical lesion Multiple frontotemporal lesions
Done
67, M, Japanese
275 mg/day for 3 days, followed by 275 mg once a week 1100 mg/day first day, followed by 275 mg once a week 275 mg/day for 3 days, followed by 275 mg once a week
Increased protein (88 mg/ dl), JC virus: positive (535,500 copies/mL of DNA) JC virus: negative
No biopsy
Kishida [15].
49, M, AfricanAmerican
Drowsiness
HIV/IRIS
HAART, steroid therapy
275 mg/day for 3 days, followed by 275 mg once a week with mirtazapine 30 mg orally daily
Yes
Cerebellar and mild cerebral atrophy, scattered, nonspecific subcortical lesions
No biopsy
Moenster [16]
74, F, unknown
Dysarthria, limb weakness
None
R frontal subcortical lesion with enhancement L parieto-occipitotemporal subcortical splenium lesion
No biopsy
McGuire [17]
Confusion, memory loss, odd behavior, wide based unsteady gait Cerebellar ataxia
250 mg/day for 3 days, followed by 250 mg once a week with mirtazapine 15 mg daily 250 mg/day for 3 days, followed by 250 mg once a week with mirtazapine 30 mg orally daily. Dose up to 500 mg weekly of mefloquine
Yes
69, M, Caucasian
Isolated CD8+ Tlymphocyte deficiencies No overt immunosuppression
Mild pleocytosis (6 cells/ mm3), JC virus: positive (911,175 copies/mL of DNA) Mild pleocytosis (21% neutrophils, 57% lymphocytes), JC virus: positive (3318 copies/mL of DNA) JC virus: positive
JC virus: positive
Done
Christakis [10]
Mild pleocytosis (8% neutrophils, 83% lymphocytes), JC virus: positive JC virus: positive (1387 copies/mL of DNA)
Done
Young [12]
No biopsy
Schröder [11]
No biopsy
Gofton [18]
No biopsy No biopsy
Kobayashi [19] Kobayashi [19]
57, M, Eurasian
None
Yes Yes
Yes
HIV/AIDS
ART
250 mg/day for 3 days, followed by 250 mg once a week
Yes
21, F, unknown
Generalized seizure
Multiple sclerosis
Natalizumab
250 mg/day for 3 days, followed by 250 mg once a week with mirtazapine 60 mg orally daily
Yes
54, F, unknown
Cerebellar ataxia
Pulmonary sarcoidosis
Prednisone 50 mg
500 mg twice weekly, followed by 250 mg once a week
Yes
47, M, Japanese
Limb weakness
Rituximab
Muscle cramp in the bilateral upper limbs
275 mg/day for 3 days, followed by 275 mg once a week 275 mg/day for 3 days, followed by 275 mg once a week
No
81, M, Japanese
Waldenström macroglobulinemia Idiopathic CD4+ lymphocytopenia
None
No
R frontal subcortical, basal ganglia, thalamic lesion with enhancement L frontal subcortical lesion with enhancement at the margin Cerebellar and brainstem lesion
R frontal subcortical lesion L fronto-parietal lesion, R parietal lobe lesion
Mild pleocytosis (95% lymphocytes), JC virus: positive (33,700 copies/mL of DNA) JC virus: positive (1200 copies/mL of DNA) JC virus: positive (2223 copies/ml of DNA)
J.-W. Shin et al. / Journal of Clinical Neuroscience xxx (2014) xxx–xxx
AIDS = acquired immunodeficiency syndrome, AML = acute myeloid leukemia, ART = active antiretroviral therapy, F = female, HAART = highly active antiretroviral therapy, HIV = human immunodeficiency virus, IRIS = immune reconstitution inflammatory syndrome, JC = John Cunningham, L = left, M = male, R = right, SLE = systemic lupus erythematosus.
3
Please cite this article in press as: Shin J-W et al. Mefloquine improved progressive multifocal leukoencephalopathy in a patient with immunoglobulin A nephropathy. J Clin Neurosci (2014), http://dx.doi.org/10.1016/j.jocn.2013.12.031
Table 1 Summary of PML treatment with mefloquine reported in the literature
4
J.-W. Shin et al. / Journal of Clinical Neuroscience xxx (2014) xxx–xxx
compounds with anti-JC virus activities, only mefloquine has shown sufficiently high penetration into the central nervous system such that it would be predicted to achieve efficacious concentrations in the brain and inhibit viral DNA replication [4]. There are reports of successful treatment using mefloquine therapy, mostly in Japanese patients (Table 1). Among the 10 patients successfully treated with mefloquine, only three had HIV/acquired immunodeficiency syndrome (AIDS) as a predisposing factor and three patients were treated with a relatively high dose of mefloquine. However, a recent American clinical trial was terminated for lack of demonstrable efficacy of mefloquine in 29 patients with HIV/ AIDS and active PML [5]. Considering this trial and other case reports, differences including genetics, dose adjustment and immune status may affect successful treatment with mefloquine. Mefloquine is substrate of the P-glycoprotein transporter, which may explain a different inter-racial drug response. In one study, oral bioavailability of immunosuppressants that are substrates for CYP3A4 isoenzymes as well as the P-glycoprotein transporter in African-Americans was between 20–50% lower than in Caucasians or non-African-Americans. Inter-ethnic variability in activity of enzymes and/or transporters may provide a common mechanism for the observed ethnic differences [6]. Some investigators suggest the intriguing possibility that genetic and environmentally-linked neuropharmacokinetic heterogeneity may play a significant role in predicting the successful response to mefloquine [7]. The neuropharmacokinetics of mefloquine may be plausibly influenced by variation in the expression and function of the P-glycoprotein transmembrane transporter with ABCB1 (MDR1) polymorphisms, a key constituent of the blood–brain barrier responsible for the active efflux of mefloquine across barrier membranes [8]. Dose adjustment of mefloquine may be another important factor in successful treatment. Among the reports of successful treatment with mefloquine, one patient was given a high initial dose (1100 mg) and another patient took an increased dose of 500 mg weekly because initial therapy of 250 mg once a week had failed [9,10]. When considering the immune status of each individual, clinical improvement from PML may be related to immune reconstitution inflammatory syndrome (IRIS), along with the effect of mefloquine. The immune response is important in removing JC virus from the brain and IRIS can occur after withdrawal of the immunosuppressive agents following a PML diagnosis [2]. Of note, in three of the 10 reported PML patients with IRIS, one patient was only completely cured after treatment with mefloquine and combined steroid therapy [11,12]. Therefore we can assume that the intensity of the immune response may contribute to the prognosis of PML. From previous results, we can assume that mefloquine may have substantial treatment efficacy in selected patients. ABCB/ MDR1 gene polymorphism may have an important role in changing central nervous system penetration or gastrointestinal absorption of mefloquine. More large studies in other ethnic groups, including polymorphism studies in the ABCB1/MDR1 gene encoding P-glycoprotein, and taking into account various underlying conditions with secondary immunosuppression should be carried out to investigate whether mefloquine is effective for treating PML.
Conflicts of Interest/Disclosures The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication. Acknowledgement This study was supported by the South Korean Ministry of Health and Welfare (A120480-1201-0000100). References [1] Aksamit AJ Jr. Progressive multifocal leukoencephalopathy: a review of the pathology and pathogenesis. Microsc Res Tech 1995;32:302–11. [2] Aksamit AJ Jr. Progressive multifocal leukoencephalopathy. Continuum (Minneap Minn) 2012;18:1374–91. [3] Berger JR, Aksamit AJ, Clifford DB, et al. PML diagnostic criteria: consensus statement from the AAN neuroinfectious disease section. Neurology 2013;80:1430–8. [4] Brickelmaier M, Lugovskoy A, Kartikeyan R, et al. Identification and characterization of mefloquine efficacy against JC virus in vitro. Antimicrob Agents Chemother 2009;53:1840–9. [5] Clifford DB, Nath A, Cinque P, et al. A study of mefloquine treatment for progressive multifocal leukoencephalopathy: results and exploration of predictors of PML outcomes. J neurovirol 2013;19:351–8. [6] Dirks NL, Huth B, Yates CR, et al. Pharmacokinetics of immunosuppressants: a perspective on ethnic differences. Int J Clin Pharmacol Ther 2004;42:701–18. [7] Nevin RL. Pharmacokinetic considerations in the repositioning of mefloquine for treatment of progressive multifocal leukoencephalopathy. Clin Neurol Neurosurg 2012;114:1204–5. [8] Nevin RL. Neuropharmacokinetic heterogeneity of mefloquine in the treatment of progressive multifocal leukoencephalopathy. Intern Med 2012;51:2257 [author reply 2259]. [9] Beppu M, Kawamoto M, Nukuzuma S, et al. Mefloquine improved progressive multifocal leukoencephalopathy in a patient with systemic lupus erythematosus. Intern Med 2012;51:1245–7. [10] Christakis PG, Okin D, Huttner AJ, et al. Progressive multifocal leukoencephalopathy in an immunocompetent patient. J Neurol Sci 2013;326:107–10. [11] Schröder A, Lee DH, Hellwig K, et al. Successful management of natalizumabassociated progressive multifocal leukoencephalopathy and immune reconstitution syndrome in a patient with multiple sclerosis. Arch Neurol 2010;67:1391–4. [12] Young BE, Yeo TR, Lim HT, et al. Progressive multifocal leukoencephalopathy with immune reconstitution inflammatory syndrome (PML-IRIS): two case reports of successful treatment with mefloquine and a review of the literature. Ann Acad Med Singapore 2012;41:620–4. [13] Naito K, Ueno H, Sekine M, et al. Akinetic mutism caused by HIV-associated progressive multifocal leukoencephalopathy was successfully treated with mefloquine: a serial multimodal MRI study. Intern Med 2012;51:205–9. [14] Hirayama M, Nosaki Y, Matsui K, et al. Efficacy of mefloquine to progressive multifocal leukoencephalopathy initially presented with parkinsonism. Clin Neurol Neurosurg 2012;114:728–31. [15] Kishida S, Tanaka K. Mefloquine treatment in a patient suffering from progressive multifocal leukoencephalopathy after umbilical cord blood transplant. Intern Med 2010;49:2509–13. [16] Moenster RP, Jett RA. Mirtazapine and mefloquine therapy for progressive multifocal leukoencephalopathy in a patient infected with human immunodeficiency virus. Am J Health Syst Pharm 2012;69:496–8. [17] McGuire JL, Fridman V, Wüthrich C, et al. Progressive multifocal leukoencephalopathy associated with isolated CD8+ T-lymphocyte deficiency mimicking tumefactive MS. J Neurovirol 2011;17:500–3. [18] Gofton T, Al-Khotani A, O’Farrell B, et al. Mefloquine in the treatment of progressive multifocal leukoencephalopathy. J Neurol Neurosurg Psychiatry 2011;82:452–5. [19] Kobayashi Z, Akaza M, Numasawa Y, et al. Failure of mefloquine therapy in progressive multifocal leukoencephalopathy: report of two Japanese patients without human immunodeficiency virus infection. J Neurol Sci 2013;324:190–4.
Please cite this article in press as: Shin J-W et al. Mefloquine improved progressive multifocal leukoencephalopathy in a patient with immunoglobulin A nephropathy. J Clin Neurosci (2014), http://dx.doi.org/10.1016/j.jocn.2013.12.031
Contents lists available at ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Review
Mefloquine improved progressive multifocal leukoencephalopathy in a patient with immunoglobulin A nephropathy Jung-Won Shin a, Keun-Hwa Jung a, Soon-Tae Lee a, Jangsup Moon a, Jung-Ah Lim a, Jung-Ick Byun a, Kyung-Il Park b, Sang Kun Lee a, Kon Chu a,⇑ a b
Department of Neurology, Seoul National University Hospital, 101 Daehang-no, Chongro-gu, Seoul 110-744, South Korea Department of Neurology, Seoul Paik Hospital, Inje University College of Medicine, Seoul, South Korea
a r t i c l e
i n f o
Article history: Received 7 August 2013 Accepted 19 December 2013 Available online xxxx Keywords: IgA nephropathy Mefloquine Progressive multifocal leukoencephalopathy
a b s t r a c t We describe a patient with immunoglobulin A nephropathy who was diagnosed with progressive multifocal leukoencephalopathy (PML) and successfully treated with mefloquine, an antimalarial medication. A 67-year-old man with immunoglobulin A nephropathy presented to the hospital emergency room with fever and generalized tonic-clonic seizure. Cerebrospinal fluid (CSF) nested polymerase chain reaction (PCR) was positive for John Cunningham virus and brain MRI displayed high signal intensity in the white matter in the right parietal lobe without gadolinium enhancement. Tapering of prednisone did not arrest the disease progression and a new lesion was detected on the cerebellum. Administration of mefloquine stopped lesion progression and resulted in dramatic clinical improvement. The CSF nested PCR for the John Cunningham virus also became negative. In reviewing the literature, mefloquine has had a heterogeneous effect in PML patients, and P-glycoprotein polymorphism and proper dosage could contribute to the various effects seen. Mefloquine may be a favorable treatment option in some patients with PML, and P-glycoprotein polymorphism may play an important role in its efficacy. More large studies in other ethnic groups including polymorphism studies for the gene encoding P-glycoprotein (ABCB1/MDR1) and taking into account various underlying conditions with secondary immunosuppression should be carried out to investigate whether mefloquine is effective for treating PML. Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
2. Case report
Progressive multifocal leukoencephalopathy (PML) presents clinically as a focal or multifocal neurologic disorder, and the disease was named for the neuropathological observation of microscopic multifocal lesions involving the white matter of the brain [1]. PML is caused by John Cunningham (JC) virus infection of the oligodendrocytes in the white matter of the brain, which leads to neurologic deficits. JC virus-induced PML is regarded as an opportunistic infection of the human nervous system [2]. Although there is no treatment proven to be effective for PML, mefloquine, a widely used antimalarial agent, has been recently reported to inhibit the JC virus infection in vitro and produce some clinical improvement. We report the beneficial effect of mefloquine in a Korean patient with PML associated with immunoglobulin (Ig) A nephropathy.
A 67-year-old right-handed man with IgA nephropathy and type 2 diabetes mellitus visited the hospital emergency room with fever and seizure. He was diagnosed with IgA nephropathy in 2004. Due to recent disease progression, he had commenced prednisone 25 mg daily in January 2013. Three months later, he presented with fever and one episode of a generalized tonic-clonic seizure. On hospital day 1, he had no neurological deficit and laboratory tests showed mild leukocytosis and elevated blood urea nitrogen (59 mg/dL, normal range: 7–20 mg/dL) and creatinine (3.56 mg/dL, normal range: 0.8–1.4 mg/dL). Brain MRI (diffusion weighted, T2weighted and fluid attenuated inversion recovery [FLAIR] imaging) displayed high intensity signal of the white matter in the right parietal lobe without gadolinium enhancement (Fig. 1). A lumbar puncture was performed and cerebrospinal fluid (CSF) analysis showed mild pleocytosis (white blood cells 82 cells/mm3, normal range: 0–3 cells/mm3, lymphocyte 57%, others 25%) with slightly elevated protein concentration (94 mg/dL, normal range: 40–85 mg/dL). Cryptococcus antigen and bacterial staining were
⇑ Corresponding author. Tel.: +82 2 2072 1878; fax: +82 2 3672 4949. E-mail address: [email protected] (K. Chu). http://dx.doi.org/10.1016/j.jocn.2013.12.031 0967-5868/Ó 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Shin J-W et al. Mefloquine improved progressive multifocal leukoencephalopathy in a patient with immunoglobulin A nephropathy. J Clin Neurosci (2014), http://dx.doi.org/10.1016/j.jocn.2013.12.031
2
J.-W. Shin et al. / Journal of Clinical Neuroscience xxx (2014) xxx–xxx
A
C
B
D
Fig. 1. Fluid attenuated inversion recovery axial MRI on presentation (A), on hospital day 9 (B) and follow-up images 2 months later (C, D). After disease progression, a new lesion developed in the bilateral cerebellum without enhancement (B) and after treatment at 2 months later, the right parietal lesion decreased and the cerebellar lesion disappeared (C, D).
negative. Generalized delta to theta activity was seen on electroencephalography. We immediately started valacyclovir 1000 mg twice a day and oxcarbazepine 450 mg twice a day. After 1 week, CSF polymerase chain reaction (PCR) tests showed negative results for herpes simplex, varicella zoster, cytomegalovirus, Epstein-Barr virus, mycobacterium, Legionella pneumophila, Mycoplasma pneumonia and BK virus. However JC virus PCR was positive, so prednisone was tapered to 7.5 mg daily. On hospital day 9, he complained of dizziness, nausea and gait disturbance. Ataxia was present in the left upper extremity on neurological examination and he showed gaze evoked nystagmus. In a follow-up brain MRI, the previous lesions had extended and a new high signal intensity lesion in the bilateral cerebellum developed on FLAIR imaging (Fig. 1). We tapered prednisone but his symptoms progressed. Therefore, on hospital day 14, we commenced mefloquine as it had been an effective therapy for PML in previous case reports. After 275 mg of mefloquine for 3 days, on hospital day 16, his symptoms stabilized and gradually improved. In a follow-up CSF examination, JC virus PCR was not detected. We continued mefloquine 275 mg once a week for 2 months and he developed no more neurological deficits and smaller brain lesions on follow-up imaging (Fig. 1).
3. Discussion JC virus-induced damage of oligodendrocytes leads to focal myelin loss and this manifests as dysfunction of the cerebral hemispheres, cerebellum or brainstem [2]. Although human immunodeficiency virus (HIV) infection remains the most common predisposing factor for PML, it can also occur as a complication of other chronic illness associated with secondary immunosuppression. As IgA nephropathy is characterized by deposition of the IgA antibody in the glomerulus, steroids and cyclophosphamide are used to preserve renal function in the high risk population. This is the first PML patient with IgA nephropathy treated by steroids to our knowledge. Berger et al. established criteria for the diagnosis of PML and recommended a diagnostic algorithm. In the algorithm, the presence of classic radiographic findings and clinical features consistent with the diagnosis coupled with a positive CSF JC virus PCR is sufficient for unequivocal diagnosis of PML [3]. Our patient satisfied these three factors. No treatments have proven to be effective for PML. The general principle of treatment is to improve the immune status. Studies have investigated drug therapy using cytosine arabinoside, cidofovir, mirtazapine, risperidone and mefloquine. Among the
Please cite this article in press as: Shin J-W et al. Mefloquine improved progressive multifocal leukoencephalopathy in a patient with immunoglobulin A nephropathy. J Clin Neurosci (2014), http://dx.doi.org/10.1016/j.jocn.2013.12.031
Patient age, sex, nationality
Initial symptoms
Comorbidity
Treatment of comorbidity
Mefloquine
Treatment response
Brain MRI
CSF analysis
Histology
Reference
55, M, Japanese
Akinetic mutism
HIV/AIDS
HAART
275 mg/day for 3 days, followed by 275 mg once a week
Yes
R frontal subcortical lesion
No biopsy
Naito [13]
60, M, Japanese
Parkinsonism
Sarcoidosis
None
Yes
Limb weakness
SLE
JC virus: negative
Done
Hirayama [14] Beppu [9]
37, M, Japanese
Psychomotor slowing, aphasia, limb weakness
AML
Prednisone 20 mg daily Ara-C/ Prednisolone
R frontal subcortical lesion R frontal subcortical lesion Multiple frontotemporal lesions
Done
67, M, Japanese
275 mg/day for 3 days, followed by 275 mg once a week 1100 mg/day first day, followed by 275 mg once a week 275 mg/day for 3 days, followed by 275 mg once a week
Increased protein (88 mg/ dl), JC virus: positive (535,500 copies/mL of DNA) JC virus: negative
No biopsy
Kishida [15].
49, M, AfricanAmerican
Drowsiness
HIV/IRIS
HAART, steroid therapy
275 mg/day for 3 days, followed by 275 mg once a week with mirtazapine 30 mg orally daily
Yes
Cerebellar and mild cerebral atrophy, scattered, nonspecific subcortical lesions
No biopsy
Moenster [16]
74, F, unknown
Dysarthria, limb weakness
None
R frontal subcortical lesion with enhancement L parieto-occipitotemporal subcortical splenium lesion
No biopsy
McGuire [17]
Confusion, memory loss, odd behavior, wide based unsteady gait Cerebellar ataxia
250 mg/day for 3 days, followed by 250 mg once a week with mirtazapine 15 mg daily 250 mg/day for 3 days, followed by 250 mg once a week with mirtazapine 30 mg orally daily. Dose up to 500 mg weekly of mefloquine
Yes
69, M, Caucasian
Isolated CD8+ Tlymphocyte deficiencies No overt immunosuppression
Mild pleocytosis (6 cells/ mm3), JC virus: positive (911,175 copies/mL of DNA) Mild pleocytosis (21% neutrophils, 57% lymphocytes), JC virus: positive (3318 copies/mL of DNA) JC virus: positive
JC virus: positive
Done
Christakis [10]
Mild pleocytosis (8% neutrophils, 83% lymphocytes), JC virus: positive JC virus: positive (1387 copies/mL of DNA)
Done
Young [12]
No biopsy
Schröder [11]
No biopsy
Gofton [18]
No biopsy No biopsy
Kobayashi [19] Kobayashi [19]
57, M, Eurasian
None
Yes Yes
Yes
HIV/AIDS
ART
250 mg/day for 3 days, followed by 250 mg once a week
Yes
21, F, unknown
Generalized seizure
Multiple sclerosis
Natalizumab
250 mg/day for 3 days, followed by 250 mg once a week with mirtazapine 60 mg orally daily
Yes
54, F, unknown
Cerebellar ataxia
Pulmonary sarcoidosis
Prednisone 50 mg
500 mg twice weekly, followed by 250 mg once a week
Yes
47, M, Japanese
Limb weakness
Rituximab
Muscle cramp in the bilateral upper limbs
275 mg/day for 3 days, followed by 275 mg once a week 275 mg/day for 3 days, followed by 275 mg once a week
No
81, M, Japanese
Waldenström macroglobulinemia Idiopathic CD4+ lymphocytopenia
None
No
R frontal subcortical, basal ganglia, thalamic lesion with enhancement L frontal subcortical lesion with enhancement at the margin Cerebellar and brainstem lesion
R frontal subcortical lesion L fronto-parietal lesion, R parietal lobe lesion
Mild pleocytosis (95% lymphocytes), JC virus: positive (33,700 copies/mL of DNA) JC virus: positive (1200 copies/mL of DNA) JC virus: positive (2223 copies/ml of DNA)
J.-W. Shin et al. / Journal of Clinical Neuroscience xxx (2014) xxx–xxx
AIDS = acquired immunodeficiency syndrome, AML = acute myeloid leukemia, ART = active antiretroviral therapy, F = female, HAART = highly active antiretroviral therapy, HIV = human immunodeficiency virus, IRIS = immune reconstitution inflammatory syndrome, JC = John Cunningham, L = left, M = male, R = right, SLE = systemic lupus erythematosus.
3
Please cite this article in press as: Shin J-W et al. Mefloquine improved progressive multifocal leukoencephalopathy in a patient with immunoglobulin A nephropathy. J Clin Neurosci (2014), http://dx.doi.org/10.1016/j.jocn.2013.12.031
Table 1 Summary of PML treatment with mefloquine reported in the literature
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compounds with anti-JC virus activities, only mefloquine has shown sufficiently high penetration into the central nervous system such that it would be predicted to achieve efficacious concentrations in the brain and inhibit viral DNA replication [4]. There are reports of successful treatment using mefloquine therapy, mostly in Japanese patients (Table 1). Among the 10 patients successfully treated with mefloquine, only three had HIV/acquired immunodeficiency syndrome (AIDS) as a predisposing factor and three patients were treated with a relatively high dose of mefloquine. However, a recent American clinical trial was terminated for lack of demonstrable efficacy of mefloquine in 29 patients with HIV/ AIDS and active PML [5]. Considering this trial and other case reports, differences including genetics, dose adjustment and immune status may affect successful treatment with mefloquine. Mefloquine is substrate of the P-glycoprotein transporter, which may explain a different inter-racial drug response. In one study, oral bioavailability of immunosuppressants that are substrates for CYP3A4 isoenzymes as well as the P-glycoprotein transporter in African-Americans was between 20–50% lower than in Caucasians or non-African-Americans. Inter-ethnic variability in activity of enzymes and/or transporters may provide a common mechanism for the observed ethnic differences [6]. Some investigators suggest the intriguing possibility that genetic and environmentally-linked neuropharmacokinetic heterogeneity may play a significant role in predicting the successful response to mefloquine [7]. The neuropharmacokinetics of mefloquine may be plausibly influenced by variation in the expression and function of the P-glycoprotein transmembrane transporter with ABCB1 (MDR1) polymorphisms, a key constituent of the blood–brain barrier responsible for the active efflux of mefloquine across barrier membranes [8]. Dose adjustment of mefloquine may be another important factor in successful treatment. Among the reports of successful treatment with mefloquine, one patient was given a high initial dose (1100 mg) and another patient took an increased dose of 500 mg weekly because initial therapy of 250 mg once a week had failed [9,10]. When considering the immune status of each individual, clinical improvement from PML may be related to immune reconstitution inflammatory syndrome (IRIS), along with the effect of mefloquine. The immune response is important in removing JC virus from the brain and IRIS can occur after withdrawal of the immunosuppressive agents following a PML diagnosis [2]. Of note, in three of the 10 reported PML patients with IRIS, one patient was only completely cured after treatment with mefloquine and combined steroid therapy [11,12]. Therefore we can assume that the intensity of the immune response may contribute to the prognosis of PML. From previous results, we can assume that mefloquine may have substantial treatment efficacy in selected patients. ABCB/ MDR1 gene polymorphism may have an important role in changing central nervous system penetration or gastrointestinal absorption of mefloquine. More large studies in other ethnic groups, including polymorphism studies in the ABCB1/MDR1 gene encoding P-glycoprotein, and taking into account various underlying conditions with secondary immunosuppression should be carried out to investigate whether mefloquine is effective for treating PML.
Conflicts of Interest/Disclosures The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication. Acknowledgement This study was supported by the South Korean Ministry of Health and Welfare (A120480-1201-0000100). References [1] Aksamit AJ Jr. Progressive multifocal leukoencephalopathy: a review of the pathology and pathogenesis. Microsc Res Tech 1995;32:302–11. [2] Aksamit AJ Jr. Progressive multifocal leukoencephalopathy. Continuum (Minneap Minn) 2012;18:1374–91. [3] Berger JR, Aksamit AJ, Clifford DB, et al. PML diagnostic criteria: consensus statement from the AAN neuroinfectious disease section. Neurology 2013;80:1430–8. [4] Brickelmaier M, Lugovskoy A, Kartikeyan R, et al. Identification and characterization of mefloquine efficacy against JC virus in vitro. Antimicrob Agents Chemother 2009;53:1840–9. [5] Clifford DB, Nath A, Cinque P, et al. A study of mefloquine treatment for progressive multifocal leukoencephalopathy: results and exploration of predictors of PML outcomes. J neurovirol 2013;19:351–8. [6] Dirks NL, Huth B, Yates CR, et al. Pharmacokinetics of immunosuppressants: a perspective on ethnic differences. Int J Clin Pharmacol Ther 2004;42:701–18. [7] Nevin RL. Pharmacokinetic considerations in the repositioning of mefloquine for treatment of progressive multifocal leukoencephalopathy. Clin Neurol Neurosurg 2012;114:1204–5. [8] Nevin RL. Neuropharmacokinetic heterogeneity of mefloquine in the treatment of progressive multifocal leukoencephalopathy. Intern Med 2012;51:2257 [author reply 2259]. [9] Beppu M, Kawamoto M, Nukuzuma S, et al. Mefloquine improved progressive multifocal leukoencephalopathy in a patient with systemic lupus erythematosus. Intern Med 2012;51:1245–7. [10] Christakis PG, Okin D, Huttner AJ, et al. Progressive multifocal leukoencephalopathy in an immunocompetent patient. J Neurol Sci 2013;326:107–10. [11] Schröder A, Lee DH, Hellwig K, et al. Successful management of natalizumabassociated progressive multifocal leukoencephalopathy and immune reconstitution syndrome in a patient with multiple sclerosis. Arch Neurol 2010;67:1391–4. [12] Young BE, Yeo TR, Lim HT, et al. Progressive multifocal leukoencephalopathy with immune reconstitution inflammatory syndrome (PML-IRIS): two case reports of successful treatment with mefloquine and a review of the literature. Ann Acad Med Singapore 2012;41:620–4. [13] Naito K, Ueno H, Sekine M, et al. Akinetic mutism caused by HIV-associated progressive multifocal leukoencephalopathy was successfully treated with mefloquine: a serial multimodal MRI study. Intern Med 2012;51:205–9. [14] Hirayama M, Nosaki Y, Matsui K, et al. Efficacy of mefloquine to progressive multifocal leukoencephalopathy initially presented with parkinsonism. Clin Neurol Neurosurg 2012;114:728–31. [15] Kishida S, Tanaka K. Mefloquine treatment in a patient suffering from progressive multifocal leukoencephalopathy after umbilical cord blood transplant. Intern Med 2010;49:2509–13. [16] Moenster RP, Jett RA. Mirtazapine and mefloquine therapy for progressive multifocal leukoencephalopathy in a patient infected with human immunodeficiency virus. Am J Health Syst Pharm 2012;69:496–8. [17] McGuire JL, Fridman V, Wüthrich C, et al. Progressive multifocal leukoencephalopathy associated with isolated CD8+ T-lymphocyte deficiency mimicking tumefactive MS. J Neurovirol 2011;17:500–3. [18] Gofton T, Al-Khotani A, O’Farrell B, et al. Mefloquine in the treatment of progressive multifocal leukoencephalopathy. J Neurol Neurosurg Psychiatry 2011;82:452–5. [19] Kobayashi Z, Akaza M, Numasawa Y, et al. Failure of mefloquine therapy in progressive multifocal leukoencephalopathy: report of two Japanese patients without human immunodeficiency virus infection. J Neurol Sci 2013;324:190–4.
Please cite this article in press as: Shin J-W et al. Mefloquine improved progressive multifocal leukoencephalopathy in a patient with immunoglobulin A nephropathy. J Clin Neurosci (2014), http://dx.doi.org/10.1016/j.jocn.2013.12.031