progressive multifocal leukoencephalopathy ( pml ) is a rare and devastating demyelinating disease of the central nervous system . the disease is caused by reactivation of a polyomavirus , the jc virus ( jcv ) , that was first described as a rare complication of chemotherapy in patients with lymphoproliferative disorders . the dramatic increase of pml incidence during the aids epidemic in the 1980s and the occurrence of pml in patients with idiopathic cd4 + lymphopenia   pointed to the importance of cd4 + t cells in the immune control of jcv infections . asymptomatic primary jcv infection actually occurs in up to 80% of the individuals , the virus remaining latent in lymphocytes and glial cells . both t- and b - cell effector functions are required to prevent viral reactivation . in autoimmune disorders , pml occurs mostly in patients with systemic lupus erythematosus ( sle ) . of note , most sle patients who develop pml have been either subjected or are concomitantly under immunosuppressant therapy ( ist ) , with a diverse combination of therapeutic regimens that causes generalized immunosuppression . steroids , azathioprine , mycophenolate mofetil , cyclophosphamide , methotrexate , thalidomide , dapsone and other specifically targeted therapies , such as rituximab or belimumab , are the treatments usually prescribed . while the main cause of pml in sle patients is likely to be therapy - related immunodeficiency , there is no correlation between the intensity of ist and pml development in sle patients , suggesting that alternative mechanisms of jcv reactivation may exist in some patients . most case reports on sle patients with pml lack data on total lymphocytes or lymphocyte subsets despite the fact that when reported , cd4 + t - cell counts are severely reduced . here a young hiv - negative portuguese female was diagnosed with sle at the age of 12 on the basis of polyarthralgias , pneumonitis , high fever and autoantibody reactivities including antinuclear antibody ( ana ) and anti - double - stranded ( ds ) dna . additional cumulative features relating to sle consisted of photosensitivity , jaccoud arthropathy , alopecia and fatigue , and ongoing positivity for anti - smith-/ribonucleoprotein , antinucleosome and antihistone , quantified at 3 + , with persistent absence of anti - ssa and anti - ssb ( euroimmun ) . case records show that in 2004 , for a period of 7 months , the anti - dsdna antibody titer fluctuated between 1/10 and 1/30 ( positive values by crithidia luciliae immunofluorescence assay ) , after which time the test became negative . thereafter , her illness was characterized by intermittent arthralgia of the small joints of the hands , knees and ankles . there was persistent hypocomplementemia and polyclonal hypergammaglobulinemia , with a high igg ( peak value 2,390 mg / dl ; upper limit of normal 1,400 ) , normal igm and iga concentrations . from 2004 to 2011 , her white blood and total lymphocyte counts ranged from 2,300 to 3,900  106/l and from 600 to 1,400  106/l , respectively , with mean counts of 3,000 and 1,000  106/l , respectively . she was not taking hydroxychloroquine and had been started on azathioprine 50 mg / day and deflazacort 6 mg / day , which were continued from 2004 to february 2012 . at her last regular follow - up visit in december 2011 she complained of decreased sensation and weakness of the right hand . there were no clinical signs of lupus disease activity with an ana titer of 1/320 , negative anti - dsdna , normal c3 ( 95.4 mg / dl ) , slightly reduced c4 of 8.25 mg / dl ( normal values 1034 ) and normal urinary sediment . in february 2012 , at the age of 34 , she complained of nausea , vertigo , limb ataxia and gait instability . at first , only slight ataxia of the right arm was noted . she was admitted to hospital and while waiting for a cerebral mri , her symptoms rapidly deteriorated with episodes of vomiting and worsened limb ataxia , which became bilateral . gadolinium - enhanced mri of the brain revealed patchy high - signal intensity lesions on t2-weighted images in the right cerebellar peduncle without diffusion restriction ( fig . 1 ) . mri angiography and a conventional cerebral angiogram showed no abnormalities of the vascular system and no signs of vasculitis . the total lymphocyte count was 800  106/l ; there was no anemia or evidence of renal or hepatic dysfunction , and ana and anti - dsdna were positive , with a low concentration of complement components c3 and c4 . blood serology was negative for herpes simplex virus , cytomegalovirus , epstein - barr virus , enterovirus , varicella - zoster virus , human t - lymphotropic virus types 1 and 2 , hiv , lyme disease and syphilis . cerebrospinal fluid examination ( csf ) revealed : ( 1 ) normal cell counts , protein , glucose , lactate , and immunoglobulin index , no oligoclonal bands and absent borrelia antibodies ; ( 2 ) negative gram stain , negative cultures for bacteria and negative microbiologic pcr for mycobacteria , herpes simplex virus , varicella - zoster virus , cytomegalovirus , epstein - barr virus , human t - lymphotropic virus types 1 and 2 , cryptococcus spp . and other fungi ; ( 3 ) negative angiotensin - converting enzyme and glial fibrillary acidic protein ; ( 4 ) negative paraneoplastic and inflammatory antibody screen ( anti - hu , yo , ri and purkinje cells , nmda receptor , ma-2 ) , mbp , mog and neuromyelitis optica , and ( 5 ) slight increase in polygonal igg and neurofilament . csf pcr was positive for jcv ( 700 copies / ml ) , which , together with the clinical data and mri findings , clinched the diagnosis of pml . steroids and treatment with cidofovir 5 mg / kg was started , the first 3 treatments 4 days apart and then every second week , to which mirtazapine 45 mg daily was added . despite these therapeutic measures , there was clinical deterioration with abnormal saccadic eye movements and failure of fixation , scanning dysarthria and more prominent gait ataxia , requiring gait assistance to prevent falls . two weeks later , a new mri showed progress of signal abnormality in the cerebellum and further extension now involving the brain stem and thalami . after 2 months , mirtazapine was reduced to 30 mg / day to avoid excess sedation , and mefloquine 250 mg / day once a week was started . clinical deterioration as well as progression of mri signal intensity in the pons and periventricular demyelination continued at 3 months after the onset of her symptoms . the patient experienced additional paresthesia on the left side of her face and swallowing difficulties . she was suffering from constant nausea , vomiting , diplopia , nystagmus , dysphagia , hemiparesthesia , right - sided hemiparesis and severe limb , gait and truncal ataxia . she also developed severe depression with mood changes , crying outbursts , despair , insomnia and loss of appetite . at 5 months after hospital admission , cd4 + levels and the cd4/cd8 ratio ranged between 262 and 381  106/l and 0.7 and 1.1  106/l , respectively . a slight initial decrease in jcv copies in the csf was followed by a further increase to 1,400 and 2 months later to 2,500 copies / ml , after which there was a continuous increase up to 3,900 copies / ml , the latter measured at 6 months after hospital admission . she was then transferred to portugal where treatment with cidofovir and cytarabine were discontinued as she suffered serious recurrent infections . at 12 months after the initial diagnosis , 3 ) , and the patient died in a persistent vegetative state 1 year after the start of her disease . sle is an autoimmune disease of unknown etiology with heterogeneous manifestations involving several organ systems , including the brain . patients with neuropsychiatric lupus may present a wide spectrum of syndromes such as headache , seizures , aseptic meningitis , stroke , psychosis , cranial neuropathy , demyelinating syndromes , movement and cognitive disorders . medication side effects , metabolic abnormalities and particularly infections can be a major cause of sle central nervous system syndromes   and were therefore investigated promptly in the diagnostic workup . our patient fulfilled the current diagnostic criteria for pml , consisting of neurological features , typical imaging and detection of jcv in the csf by pcr . visual disturbances , motor weakness , altered mental state and sensory deficit remain the most common ones , whereas symptoms due to mass effect or epilepsy are quite rare . mri is the most sensitive imaging method for the investigation of suspected pml , typical lesions appearing hyperintense on fluid - attenuated inversion recovery and t2-weighted sequences . in our patient , initial suspicion of peripheral nerve entrapment delayed the diagnostic workup , as a consequence of which therapy was instituted at a late stage , the latter probably contributing to refractoriness to therapy , with a relentless clinical deterioration reflected by increasing mri lesions , leading to death . increased susceptibility to severe bacterial infections has been described in association with lymphopenia defined by < 1,000 lymphocytes 106/l . lymphopenia in sle is usually regarded as a disease manifestation , targeting lymphocytes or their precursors as an expected side effect of ist . however , interestingly , lymphopenia has been observed in up to 70% of the untreated patients at disease onset , suggesting that it may be a promoter rather than a consequence of the sle disease process . there are no current recommendations for the investigation and treatment of sle patients with severe or persistent lymphopenia , in the absence or presence of ist . as a result , lymphopenia is frequently ignored in clinical practice when we believe that instead it should constitute a major clinical concern . these essentially support maintaining a lymphocyte count > 1,000 lymphocytes 106/l , exclusion of infections and lymphoproliferative disease , and principally advocate adjustment of ist without proposing replacement therapies . our patient presented with very low cd4 + t - cell counts and a low cd4/cd8 t - cell ratio , which most likely contributed to the jcv reactivation . treatment of sle patients with pml should eliminate the virus and increase lymphocyte counts without aggravating any sle manifestations . highly active antiretroviral therapy has reduced mortality rates in hiv - positive patients with pml . cidofovir , an antiviral nucleotide analogue , showed some efficacy in the treatment of hiv - positive patients with pml but it has been unsuccessful in hiv - negative patients . cytarabine , a chemotherapy agent ( nucleoside arabinoside ) , has been one of the most frequently used drugs despite commonly encountered adverse effects of nausea and bone marrow toxicity , but a randomized controlled trial of cytarabine in 57 patients did not show any efficacy in treating hiv - positive subjects with pml , whereas another study reported positive clinical efficacy results in 7/19 ( 36% ) of the patients . mirtazapine was added to her therapy because in vitro studies have suggested a role for the 5-ht2a receptors acting as the receptor for jcv in glial cells in the brain . we added mefloquine , a widely used antimalarial drug that showed some efficacy in inhibiting the jcv infection be cause of in vitro data as well as clinical improvement in patients with pml . a clinical case study with a combination of the antiviral agent cmx001 , an oral formulation of cidofovir and recombinant human interleukin-7 ( cyt107 ) , an inducer of cd4 + and cd8 + t cells , reported successful treatment in pml . unfortunately , these investigational drugs were not available at the time our patient required treatment . current guidelines on the treatment of sle suggest that antimalarials may be of benefit in sle patients without major organ manifestations . we were unable to understand why the patient was not on hydroxychloroquine , which may have provided symptomatic control for the arthralgia and spared her from ist . jc polyomavirus screening for pml risk stratification in patients under ist should perhaps be extended to sle patients with longstanding lymphopenia in order to prevent viral reactivation in this setting . jcv infection should be considered at the onset of neuropsychiatric symptoms , total lymphocyte and lymphocyte subset counts should be performed at regular intervals and , most importantly , ist leading to lymphopenia should be avoided for as long as possible . the patient 's partner has agreed to the publication by written consent . despite several attempts , the authors declare that there are no conflicts of interest regarding the publication of this paper .
progressive multifocal leukoencephalopathy ( pml ) caused by reactivation of the jc virus ( jcv ) , a human polyomavirus , occurs in autoimmune disorders , most frequently in systemic lupus erythematosus ( sle ) . 
 we describe a hiv - negative 34-year - old female with sle who had been treated with immunosuppressant therapy ( ist ; steroids and azathioprine ) since 2004 . in 2011 
 , she developed decreased sensation and weakness of the right hand , followed by vertigo and gait instability . 
 the diagnosis of pml was made on the basis of brain mri findings ( posterior fossa lesions ) and jcv isolation from the cerebrospinal fluid ( 700 copies / ml ) . 
 ist was immediately discontinued . 
 cidofovir , mirtazapine , mefloquine and cycles of cytarabine were sequentially added , but there was progressive deterioration with a fatal outcome 1 year after disease onset . 
 this report discusses current therapeutic choices for pml and the importance of early infection screening when sle patients present with neurological symptoms . in the light of recent reports of pml in sle patients 
 treated with rituximab or belimumab , we highlight that other ist may just as well be implicated . 
 we conclude that severe lymphopenia was most likely responsible for jcv reactivation in this patient and discuss how effective management of lymphopenia in sle and pml therapy remains an unmet need .