Background Progressive multifocal leukoencephalopathy (PML) is a deadly demyelinating disease of the brain, caused by reactivation of the polyomavirus JC (JCV). PML has classically been described in individuals with profound cellular immunosuppression such as patients with AIDS, haematological malignancies, organ transplant recipients or those treated with immunosuppressive or immunomodulatory medications for autoimmune diseases.
Methods and case reports The authors describe five HIV seronegative patients with minimal or occult immunosuppression who developed PML including two patients with alcoholic cirrhosis, one with untreated dermatomyositis and two with idiopathic CD4+ T cell lymphocytopenia. The authors performed a review of the literature to find similar cases.
Results The authors found an additional 33 cases in the literature. Of a total of 38 cases, seven (18.4%) had hepatic cirrhosis, five (13.2%) had renal failure, including one with concomitant hepatic cirrhosis, two (5.2%) were pregnant women, two (5.2%) had concomitant dementia, one (2.6%) had dermatomyositis, and 22 (57.9%) had no specific underlying diagnosis. Among these 22, five (22.7%) had low CD4+ T cell counts (0.080–0.294×109/l) and were diagnosed as having idiopathic CD4+ lymphocytopenia, and one had a borderline CD4+ T cell count of 0.308×109/l. The outcome was fatal in 27/38 (71.1%) cases within 1.5–120 months (median 8 months) from onset of symptoms, and 3/4 cases who harboured JCV-specific T cells in their peripheral blood had inactive disease with stable neurological deficits after 6–26 months of follow-up.
Discussion These results indicate that PML can occur in patients with minimal or occult immunosuppression, and one can revisit the generally accepted notion that profound cellular immunosuppression is a prerequisite for the development of PML.
- progressive multifocal leukoencephalopathy
- JC virus
- idiopathic CD4+ T cell lymphocytopenia
- infectious diseases
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- progressive multifocal leukoencephalopathy
- JC virus
- idiopathic CD4+ T cell lymphocytopenia
- infectious diseases
Progressive multifocal leukoencephalopathy (PML) is an often lethal demyelinating disease of the brain, caused by the human polyomavirus JC (JCV).1 Approximately 85% of the adult population has antibodies against JCV, and primary infection is asymptomatic. A profound suppression in cellular immunity has classically been recognised as the absolute requirement for reactivation of JCV, which subsequently can spread to the central nervous system and cause lytic infection of oligodendrocytes, leading to PML. Nowadays, approximately 79% of PML patients have AIDS, 13% have haematological malignancies, 5% are organ-transplant recipients, and 3% have autoimmune diseases treated with immunosuppressive or immunomodulatory medications.2
However, PML may also occur in patients with minimal or occult immunosuppression, which makes diagnosis particularly challenging. We describe five cases of PML and perform a review of the literature on this topic, which reveals 33 other cases.3–32 Altogether, with these 38 cases, one can revisit the generally accepted notion that severe immunodepression is an absolute prerequisite for the development of PML.
We used the following search terms in PUBMED to find PML cases with minimal or occult immunosuppression: PML, JC virus and immunosuppresion, immunocompetent, case reports, primary or spontaneous PML and idiopathic CD4+ T-cell lymphocytopenia. Cases were excluded if the patient had HIV infection, haematological disease (leukaemias, lymphomas, Waldenstrom macroglobulinemia, Wiskot–Aldrich syndrome, common variable immunodeficiency, hypogammaglobulinemias) or ongoing cancer, received recent chemotherapy, had auto-immune disease treated with oral or parenteral immunosuppressive or immunomodulatory medications, or was a transplant recipient. We also excluded patients with untreated systemic lupus erythematosus or granulomatoses (tuberculosis and sarcoidosis). Cases were also excluded when a diagnosis of PML led to the concomitant or subsequent discovery of a disease with known association with PML or when other opportunistic infections or tumours were present. Remaining cases were included only if PML was confirmed by positive JCV PCR in cerebrospinal fluid (CSF), or characteristic features of PML on biopsy or autopsy. Using these criteria, we could identify another 33 cases. Detection of JCV-specific CD8+ cytotoxic T lymphocytes in blood in four out of our five cases was performed as previously described.33
A 50-year-old man with history of alcoholic cirrhosis and oesophageal varices presented with difficulties speaking, gait unstability and blurred vision. He had discontinued alcohol consumption 3 years previously and was not taking any medication. The neurological exam showed severe dysarthria and scanned speech, horizontal nystagmus and bilateral saccadic pursuit. Reflexes were increased in the left upper extremity, and he had bilateral dysmetria and gait ataxia. Vibration sense was decreased in both feet. An MRI of the brain showed a 2 cm area of hyperintensity on FLAIR images in the left brachium pontis, extending into the left cerebellar hemisphere, a smaller lesion in the right cerebellar hemisphere and one lesion in the right corona radiata. There was no mass effect or contrast enhancement in T1-weighted images. He had mild leucopenia at 3.5×109/l (51.5% neutrophils, 33.1% lymphocytes, 11.6% monocytes, 3.2% eosinophils), platelets were decreased at 70×109/l, and liver function tests were normal. HIV serology was negative, and a T cell subset analysis showed CD4+ count of 0.472×109/l and CD8+ count of 0.222×109/l with a CD4/CD8 ratio of 2.12. The CSF exam showed 0 WBC and 0 RBC, concentration of protein was 280 mg/l and glucose 3.05 mmol/l. PCR for JCV DNA was negative in CSF. However, because of the clinical and radiological presentation, PML was suspected, and the patient was treated with mirtazapine 15 mg/day.34 Two months later, a repeat MRI showed an increase in size of the cerebellar lesions in FLAIR, and there was no enhancement in T1-weighted images after administration of gadolinium (figure 1A,B). JCV PCR was negative again in a second CSF sample. Brain biopsy of the right frontal lobe lesion confirmed the diagnosis of PML by positive immunohistochemistry (IHC) for JCV proteins, and quantified PCR on fresh frozen brain sample showed a JC viral load of 3.96×107 copies/μg brain DNA. JCV-specific T cells were detectable in his blood. His condition stabilised, and a follow-up MRI 8 months later showed transient speckled contrast enhancement of the lesions. Twenty-six months after the onset of symptoms, he still has a persistent bilateral cerebellar syndrome. His current CD4+ T cell count is 0.730×109/l.
A 64-year-old man with history of alcoholic cirrhosis and eosophageal varices presented with left facial tingling and numbness, followed by a 1-month history of progressive left-sided weakness. He had been sober for 1 month. An MRI of the brain showed right parietotemporal and frontotemporal hyperintense lesions on FLAIR images. The CSF exam was normal, but JCV PCR was not performed. WBC count was 9.4×109/l with 90.6% neutrophils, 3.8% lymphocytes, 3.3% monocytes, 0.3% eosinophils and 0.1% basophils. A right thalamic brain biopsy was complicated by intraparenchymal haemorrhage with mass effect, and dexamethasone treatment was initiated. Histological exam confirmed the diagnosis of PML and dexamethasone was quickly tapered off. HIV serology was negative, and the CD4+ T cell count was 0.240×109/l. JCV specific T cells were detectable in his blood. A lumbar puncture demonstrated a JC viral load of 1285 copies/ml. He was started on mirtazapine 15 mg/day. After 2 months, a follow-up lumbar puncture showed a negative JCV PCR, and a repeat CD4+ lymphocyte count was 0.732×109/l. Currently, 8 months after onset of symptoms, he has made a remarkable recovery with minimal residual left-sided hemiparesis.
A 29-year-old woman, with history of dermatomyositis, treated with hydroxychloroquine for 4 weeks 14 months previously, presented with left arm numbness and weakness, and left leg weakness. She was not taking any medication. The neurological exam showed a mild left hemiparesis. She had mild leucopenia with a WBC count of 3.9×109/l initially, which normalised at 4.9×109/l 6 days later. An MRI of the brain showed a hyperintense signal in FLAIR sequences in the right thalamus, which remained isointense without any enhancement in T1-weighted images after administration of gadolinium (figure 1C,D). Another lesion was present in the right frontal-lobe white matter. Because an inflammatory demyelinating disorder was suspected, she received 1 g of methylprednisolone intravenous/day for 5 days, which did not improve her symptoms. A deltoid muscle biopsy showed perivascular atrophy, T-cell macrovasculopathy and severe myopathic change. Two months later, she developed horizontal nystagmus, followed by diplopia and increased left-sided weakness. The neurological exam showed right III and VI cranial nerve paresis, a left cortical hand syndrome and left leg weakness. The WBC count was 4.5×109/l. A repeat MRI did not show any new lesions. She again received methylprednisolone 1 g/day intravenous for 5 days, followed by oral prednisone. A complete work-up for malignancies, infectious and other autoimmune diseases was negative. A stereotactic brain biopsy of the right thalamic lesion established the diagnosis of PML. Oral corticosteroids were tapered off, and mirtazapine 15 mg/day was started. The CD4+ T cell count was 0.559×109/l, and the HIV serology was negative. She had detectable JCV-specific T cells in her blood. Six months after the onset of neurological symptoms, she had made a remarkable recovery of the right III and VI paresis, and had partial improvement of her left hemiparesis, allowing her to walk unassisted. Her current WBC count is 4.2×109/l.
A 49-year-old man without any significant past medical history presented with slowly progressive word-finding difficulties. On neurological exam, he had an expressive aphasia. MRI of the brain showed a hyperintense signal in FLAIR and a corresponding hypointense signal in T1-weighted images in the subcortical white matter of both frontal which did not enhance after administration of gadolinium (figure 1E,F). A biopsy of the left frontoparietal region established the diagnosis of PML. HIV serology was negative, and HIV RNA was undetectable in his blood, but he had a low CD4+ count of 0.080×109/l and a CD8+ count of 0.5×109/l with a CD4/CD8 ratio of 0.16. Protein electrophoresis and bone marrow biopsy did not reveal a causative factor for the low CD4 count. Twenty months after the onset of symptoms, the patient is still slowly worsening and has an expressive aphasia, apraxia and bilateral pyramidal syndrome. Repeat MRI showed progression of the lesions and atrophy of the left frontal lobe. JCV-specific lymphocytes were detected in his blood, and he was started on mirtazapine 15 mg/day.
A 61-year-old man with a history of syphilis 2 years previously and psoriasis, which was treated with topical corticosteroids, presented with progressive word-finding difficulties and right-sided weakness. On neurological exam, he had expressive aphasia, right-leg paresis and right-arm paralysis. An MRI of the brain showed a left frontoparietal white-matter lesion on T2-weighted images, which extended through the corpus callosum to the other hemisphere, and a small lesion in the left brainstem. There was no contrast enhancement or mass effect. The HIV serology was negative. The CSF exam was unrevealing, and JCV PCR was negative. However, a left frontal stereotactic biopsy, done 4 months after the onset of symptoms, established the diagnosis of PML. Two months later, the patient was rehospitalised with an acute renal insufficiency and serum creatinine at 985.6 μmol/l (54.56–100.32). The WBC count at that time was 6.17×109/l with 14.9% lymphocytes, and the CD4+ count was 0.294×109/l. On ultrasound, he had bilateral hydronephrosis, and a CT scan showed left ureteritis. The urine culture was negative, and no treatment was given. Urine PCR showed JCV but no BKV DNA. He underwent one haemodialysis treatment for hyperkaliemia, after which there was fast and spontaneous improvement of the kidney function. He was then started on interferon alpha 3×106 IU subcutaneously every 2 days as treatment for PML, which was continued for 9 months. Now, 5 years after the onset of symptoms, he has made a remarkable recovery and only has a discrete right-arm paresis and word-finding difficulties.
Results and review of literature
We found 33 other cases of PML with minimal or occult immunosuppression published in the literature from 1966 to 2009 (table 1). Of these, 14 were HIV-seronegative, and 19 had not been tested (marked by an asterisk in table 1), including 12 diagnosed as having PML before the beginning of the AIDS epidemic in 1984.3–32 There were five patients with kidney disease (no 1–5),4 11 14 19 20 five patients with liver disease (no 5–8 and no 10),5 13 20 27 30 two pregnant women (no 13–14),22 24 two patients with dementia (no 15–16)16 32 and 20 other cases (no 9, no 11–12 and no 17–33).3 6–10 12 15 17 18 21 23 25–29 31 Of note, case no 5 had kidney failure and liver cirrhosis, and is therefore counted once in each category. Among these 20 cases, 14 had normal or high WBC counts (no 9, no 11–12, no 19, no 20–21, no 24–29, no 31 and no 33), one had low total lymphocytes counts (no 17), and four had low or borderline low CD4+ T cell counts (0.08–0.308×109/l) (no 18, no 22–23 and no 30). One of these 20 cases gives no information about white blood cell count (no 32).
Of a total of 38 cases, seven (18.4%) had hepatic cirrhosis, five (13.2%) had chronic renal failure, two (5.2%) were pregnant women, two (5.2%) had concomitant dementia, one (2.6%) had dermatomyositis, and 22 (57.9%) had no specific underlying diagnosis. Among these 22, five (22.7%) had low CD4+ T cell counts (0.080–0.294×109/l) and were diagnosed as having idiopathic CD4+ lymphocytopenia. The outcome was fatal in 27/38 (71.1%) cases within 1.5–120 months from the onset of symptoms (median 8 months).
The 38 patients reported in our series and in the review of the literature did not have classic risk factors for development of PML. Indeed, it is commonly thought that most PML patients have a severe deficit in cellular immunity. Furthermore, we and others have previously demonstrated that the cellular immune response, mediated by CD4+ and CD8+ T lymphocytes, plays a crucial role in the containment of JCV. However, transient or discrete failure in cellular immunity might be enough to promote JCV reactivation. Chronic disease such as hepatic cirrhosis, caused by alcohol, hepatitis C infection or malnutrition, as well as kidney failure may cause immunosuppression.
Indeed, hepatic cirrhosis can lead to portal hypertension and hypersplenism, with subsequent leucopenia as white blood cells are sequestrated in the enlarged spleen. Furthermore, cirrhosis also leads to hypogammaglobulinemia. Cirrhosis was indeed the underlying condition in seven PML patients in our study, and leucopenia, lymphocytopenia or CD4+ T lymphocytopenia was documented in three of them. It is well known that cirrhotic patients have a higher risk of developing bacterial infections, and 30–50% of deaths among cirrhotic patients are directly caused by infections. Immune dysfunction in hepatic disease may be caused by altered cytokine production, impaired cellular immune response and vascular disturbances, which lead together to increased susceptibility to infections.35
Chronic renal failure has also been associated with immunosuppression and higher risk of infections. These patients have reduced responses to most vaccines incriminating T-cell dysfunction. In addition, haemodialysis patients have impaired lymphocyte proliferation and reduced production of activation-dependent cytokines in vitro possibly caused by deficient antigen-presenting cells. Furthermore, these patients have a marked decrease in IL-2 production, and an impaired T-cell proliferation (reviewed in36 37). Often, encephalopathic changes are thought to be caused by prolonged haemodialysis, but Matsubara et al suggested that some of the cases of progressive dialysis encephalopathy might in fact be PML.19 Of note, one patient with chronic renal failure was HTLV-I-seropositive but did not have adult T cell leukaemia (no 5). Therefore, the contribution of HTLV-I infection to PML development remains unclear.
Our dermatomyositis patient (case 3) also illustrates the fact that rheumatological disease in and of itself can be a predisposition to develop PML, even in the absence of immunosuppressive treatment. In a recent review of 36 PML patients with rheumatological diseases, only one with systemic lupus erythematosus had not been treated with any immunosuppressive medications.38 Similarly, our patient had not been on any treatment for more than a year, contrary to other patients with dermatomyositis who developed PML while receiving immunosuppressive medications.39 40 Of note, she had a mild and transient leucopenia each time she presented with new neurological symptoms. However, her CD4+ T-cell counts were in the normal range at the time of PML diagnosis.
Interestingly, of these 38 patients with PML, 22 (57.9%) had not been diagnosed as having any specific underlying disease up to the development of PML. Among these, five patients were found to have idiopathic CD4+ lymphocytopenia (ICL) (CD4+ count <0.300×109/l). One hepatitis B carrier had a borderline CD4+ count of 0.308×109/l. DeHovitz et al reported that six out of 248 (2.4%) HIV seronegative sexually active women without history of intravenous drug use had transiently CD4+ T-cell counts of less than 0.35×109/l which normalised several months later. In a larger population of 633 women (92% of whom were black), 20% consistently had low total white blood cell counts, and so the authors speculate that at any given time 0.4–4.1% of these women would have low CD4+ T-cell counts.41 Patients with ICL often are asymptomatic, but then suddenly develop an opportunistic infection. A thorough search must be done for associated disorders. Zonios et al followed a cohort of 39 patients with ICL and found that 15 patients contracted an opportunistic infection, and four developed an autoimmune disease upon follow-up.42
Pregnancy is a classic state of relative immunosuppression. Among 71 pregnant women, those who had an increase in their JCV and BKV antibody titre in the third trimester had lower lymphocyte counts. One can hypothesise that a decrease in the cellular immune response led to viral reactivation and a subsequent increase in humoral immune response in these women.43 Interestingly, the two pregnant women who developed PML did not have documented leucopenia.
Two 75–80-year-old PML cases had Alzheimer's disease as the sole predisposing disease. However, three other patients, aged 63–70, were clinically suspected of having a degenerative disease due to their age and clinical presentation (no 19, no 24 and no 28). One can only speculate that age-associated immunosuppression allowed JCV reactivation in these cases. Of note, T cell subsets were not available.
There are several limitations to our study. First, 19 patients were not tested for HIV. It is therefore possible that some of these had unrecognised HIV infection as a predisposing factor for PML. However, this is unlikely, since 12 of them were diagnosed as having PML before the AIDS epidemic, 16 had an autopsy showing no features consistent with HIV-infection, and 14 had none of the typical haematological abnormalities of AIDS. Second, not all patients reported in table 1 had a thorough work-up to uncover causes of immunosuppression during their lifetime, since the diagnosis of PML was only established at autopsy in many of them. Third, T cell subsets were not available in 24 out of the 33 cases found in literature, and it is possible that the diagnosis of ICL was overlooked in several of these cases.
In conclusion, clinicians should be aware that PML can occur in patients with minimal or occult immunosuppression. In those patients, JCV CSF PCR is warranted if they have a progressive neurological disorder associated with non-enhancing brain lesions that do not respect vascular territories. If JCV PCR is negative, a brain biopsy should be performed to establish the diagnosis, as was the case of our patient with alcoholic cirrhosis (case 1) and one of the patients with ICL (case 5).
There is no specific treatment for PML. Therefore, the most important therapeutic intervention is to identify, and if possible correct, the underlying cause of immunosuppression. In fact, out of the four tested PML patients in this study, all were able to mount a detectable cellular immune response against JCV, and three of them now have an inactive disease clinically and radiologically, 6–26 months from disease onset.
Funding This study was supported in part by NIH grants R01 NS 041198 and 047029 and K24 NS 060950 to IJK, and T32 CA09031-32 to SG.
Competing interests None.
Ethics approval Ethics approval was provided by the Beth Israel Deaconess Medical Center.
Provenance and peer review Not commissioned; externally peer reviewed.
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