Symptoms Of Progressive Multifocal Leukoencephalopathy Research Articles

Treating sarcoidosis-associated progressive multifocal leukoencephalopathy with infliximab.

Although most of the progressive multifocal leukoencephalopathy cases in sarcoidosis patients are explained by the treatment with immunosuppressive drugs, it is also reported in treatment-naive sarcoidosis patients, which implies a general predisposition of sarcoidosis patients for progressive multifocal leukoencephalopathy. Indeed, it was shown that active sarcoidosis patients have increased regulatory T cell frequencies which could lead to a subsequent systemic immunosuppression. However, if sarcoidosis with systemic changes of T cell subsets frequencies constitute a risk factor for the development of progressive multifocal leukoencephalopathy, which could then be counteracted by sarcoidosis treatment, is not known. In this cohort study, we included, characterized and followed-up six patients with bioptically confirmed definite progressive multifocal leukoencephalopathy and definite or probable sarcoidosis presenting between April 2013 and January 2019, four of them had no immunosuppressive therapy at the time of developing first progressive multifocal leukoencephalopathy symptoms. Analysis of immune cell subsets in these patients revealed significant imbalances of CD4+ T cell and regulatory T cell frequencies. Due to the progression of progressive multifocal leukoencephalopathy in four patients, we decided to treat sarcoidosis anticipating normalization of immune cell subset frequencies and thereby improving progressive multifocal leukoencephalopathy. Notably, by treatment with infliximab, an antibody directed against tumour necrosis factor-α, three patients continuously improved clinically, JC virus was no longer detectable in the cerebrospinal fluid and regulatory T cell frequencies decreased. One patient was initially misdiagnosed as neurosarcoidosis and died 9 weeks after treatment initiation due to aspiration pneumonia. Our study provides insight that sarcoidosis can lead to changes in T cell subset frequencies, which predisposes to progressive multifocal leukoencephalopathy. Although immunosuppressive drugs should be avoided in progressive multifocal leukoencephalopathy, paradoxically in patients with sarcoidosis treatment with the immunosuppressive infliximab might restore normal T cell distribution and thereby halt progressive multifocal leukoencephalopathy progression.

Immune checkpoint inhibitors for progressive multifocal leukoencephalopathy: Identifying relevant outcome factors

Progressive multifocal leukoencephalopathy (PML) is an infectious brain disease caused by JC virus in immunocompromised individuals. Immune checkpoint inhibitors (ICIs) recently emerged as a therapeutic hope for these patients but identification of those likely to respond to the treatment is still an unmet need. We performed a systematic PubMed search for reports of patients treated for PML using an ICI. Clinical, biological and radiological characteristics were contrasted between patients who responded to the treatment (RP) and those who did not (NRP). Thirty-five patients were included in the present study. Twenty-one of them reportedly benefited from the treatment. Age, blood CD4+ cells count, pretreatment viral load in the cerebrospinal fluid (CSF), PML lesions localization, treatment delay since first PML symptoms, type of ICI used and immune-related adverse events (irAEs) occurrence did not significantly differ between RP and NRP. By contrast, a history of therapeutic immune suppression and the use of an immunosuppressive therapy at treatment initiation were significantly associated with a poor response. Besides, reaching an undetectable viral load in the CSF and reduction of the lesion load on magnetic resonance imaging after ICI administration was associated with a good clinical response. Current data suggest that patients with PML under immunosuppressive therapy are less likely to respond to ICIs and raises the issue of the optimal management of irAEs during ICI treatment in this setting.

Pembrolizumab for treatment of progressive multifocal leukoencephalopathy in primary immunodeficiency and/or hematologic malignancy: a case series of five patients

Progressive multifocal leukoencephalopathy is a rare opportunistic infection of the brain by John Cunningham polyomavirus in immune-compromised patients. In cases where no overt option for immune reconstitution is available [e.g., in patients with primary immunodeficiency (PID)], the disease is lethal in the majority of patients. Immune checkpoint inhibition has been applied in recent years with mixed outcomes. We present four novel patients and the follow-up of a previously published patient suffering from progressive multifocal leukoencephalopathy (PML) due to PID and/or hematologic malignancy who were treated with the immune checkpoint inhibitor pembrolizumab. In two patients with PID, symptoms improved and stabilized. One patient died because of worsening PML another of intracranial hemorrhage which was unrelated to PML or its treatment with pembrolizumab. The fifth patient suffered from PID and died of a pre-existing immune dysregulation, possibly exacerbated by pembrolizumab. The long-term follow-up of the first patient provides support for therapeutic decisions during this therapy and is the longest published clinical course of a patient with checkpoint inhibition for PML. We conclude that pembrolizumab can control PML symptoms long term in a subgroup of patients with PID, in our cases for 21 and 36 months. However, therapy must be started early because symptoms are only partially reversible. In light of severe adverse events, application of pembrolizumab is only justified if the prognosis for the individual patient is very poor.

BK polyomavirus associated progressive multifocal leukoencephalopathy in a person living with HIV

Progressive multifocal leukoencephalopathy (PML) is a rare demyelinating disease of the white matter central nervous system occurring in immunocompromised patients particularly those with T cell deficiency such as in HIV, haematological and solid organ malignancies and those taking immunomodulatory medications. PML is caused by JC virus however in rare cases BK virus has been isolated in the cerebral spinal fluid of patients presenting with PML.In this case we describe a 49 year old man who presented to the emergency department with a 2 week history of progressive right sided weakness and dysarthria. His background history included HIV diagnosed in 2005, he had not engaged with care in the past 2 years and had not been taking anti-retroviral therapy (ART). Other past medical history included untreated hepatitis C. His CD4 count was 90 (11%) cells/mm3 on admission and his HIV viral load VL) was 141,000 copies/ml. Magnetic resonance imaging(MRI) showed a hypointense lesion on T1, hyperintense on T2 and FLAIR without diffusion restriction and without mass effect. A lumbar puncture was performed which confirmed JC virus was positive (PCR <50 copies/ml) and also revealed BK virus was positive (PCR 46,511 copies/ml). The patient was commenced on tenofovir alafenamide fumarate/emtricitabine/darunavir/cobicistat in combination with dolutegravir 50mg twice daily. On day 40 post commencement of ART the patient was readmitted with worsening of his right arm weakness and dysarthria. A repeat MRI was performed which showed the hyperdense lesion on T2 and FLAIR appeared slightly larger with some slight enhancement with gadolinium contrast but no other features suggesting PML immune reconstitution inflammatory syndrome (IRIS). The CD4 count had increased to 141(17%) and HIV VL had decreased to 85 copies/ml. A clinical diagnosis of PML IRIS was made and the patient was commenced on prednisolone 30mg BD which lead to an initial improvement in symptoms.Interestingly in this case, both JC virus and BK virus were detected in the CSF of this patient with the level of JC virus being too low to quantify. BK virus was not detectable on peripheral serum sampling suggesting that BK virus is replicating in the CNS independent of other body sites. There have been 5 case reports in the literature of BK virus as the cause of PML.Testing for BK virus should be considered in patients presenting with signs and symptoms of PML and encephalitis particularly when no other cause is found.

Ocrelizumab Treatment in Patients with Primary Progressive Multiple Sclerosis: Short-term Safety Results from a Compassionate Use Programme in Germany

ObjectivesIn January 2018, the European Union (EU) approved ocrelizumab in relapsing multiple sclerosis (RMS) and as the first disease-modifying therapy (DMT) for patients with primary progressive multiple sclerosis (PPMS) with efficacy proven in a phase 3 randomised controlled trial. Eleven months prior to the European regulatory approval, a compassionate use programme (CUP) made ocrelizumab available to 489 patients with PPMS in Germany, thereby for the first time providing a therapeutic option to patients with PPMS who could not participate in ocrelizumab studies. Here, we report real-world patient characteristics and short-term safety data of patients with PPMS treated with ocrelizumab in this CUP. Patients and methodsThis CUP was initiated in February 2017 – shortly before US Food and Drug administration approval in March 2017 – and ended in January 2018, following ocrelizumab approval in the EU. Adult patients (age ≥18 years) with PPMS who had a positive benefit/risk ratio according to the treating physician were eligible for inclusion at German treatment centres. The main exclusion criteria were current/recent treatment with other immune therapies and unresolved/chronic/active infections. Patients received methylprednisolone and an antihistamine before treatment with intravenous ocrelizumab in 6-month cycles. The first ocrelizumab dose was a 300 mg infusion followed by a second 300 mg infusion 2 weeks later; subsequent doses were delivered as a single 600 mg infusion. Adverse events were reported immediately. ResultsOf 580 requests received from 104 centres, 525 patients met the eligibility criteria. Thirty-five patients did not participate due to withdrawal by the treating physician, and one due to death prior to treatment. A total of 489 patients received at least one 600 mg dose of ocrelizumab (administered as two 300 mg infusions) and 51 received a second dose. Due to termination of the CUP upon marketing authorisation, the maximum follow-up period was 12 months. Median patient age was 52 years (range: 24–73), and 49% were female. Previous immunomodulatory or immunosuppressive therapies had been received by 41% of patients, with the most commonly used being glucocorticoids, mitoxantrone, interferon-β and glatiramer acetate. Patients with a previous malignancy, serious disease or infection (42 patients, 9%) had recovered from this prior to the CUP. Nine serious adverse events and 70 non-serious adverse events were reported in 40 patients. Adverse event categories were generally consistent with the known safety profile of ocrelizumab; one patient had carry-over progressive multifocal leukoencephalopathy (PML) due to previous natalizumab treatment. ConclusionThis CUP provides first real-world observations of ocrelizumab for the treatment of PPMS in a large patient cohort in Germany, supporting that ocrelizumab is generally well-tolerated in clinical practice. Physicians should be vigilant for early symptoms of PML, as to date, 9 PML cases that were all confounded have been reported in patients treated with ocrelizumab worldwide, with 8 carry-over cases from a prior DMT.

Brentuximab Vedotin in Combination with Nivolumab, Doxorubucin, and Dacarbazine in Newly Diagnosed Patients with Advanced Stage Hodgkin Lymphoma

Brentuximab Vedotin in Combination with Nivolumab, Doxorubucin, and Dacarbazine in Newly Diagnosed Patients with Advanced Stage Hodgkin Lymphoma

Progressive multifocal leukoencephalopathy in HIV-infected patients: clinical features and diagnosis (literature review)

Progressive multifocal leukoencephalopathy (PML) is one of the most severe opportunistic diseases of the central nervous system, which leads to multiple demyelination of brain structures, neurological symptoms and frequent death or disability of the patient. The etiological factor of this disease is Human polyomavirus 2 (JCPyV).This pathogen is widespread – antibodies are found in 80% of the world›s population. However, the clinical symptoms of this infection appear only in people with a pronounced decline in cellular immunity. Until 1980 progressive multifocal leukoencephalopathy was extremely rarely diagnosed. Now days the main cause of the clinical symptoms of PML is immunodeficiency caused by HIV infection. Clinical manifestations of PML are characterized by various non-specific neurological symptoms, similar to other lesions of the central nervous system, the symptoms progress slowly over several months, and usually lead to death. Diagnosis of PML is based on laboratory and instrumental methods, such as DNA JCPyV detection in the cerebrospinal fluid, brain biopsy, and radiation diagnostic methods. There is no effective prevention and etiotropic therapy for PML. Improved parameters of cellular immunity and antiretroviral treatment in HIV positive patients significantly increase the life expectancy of patients with PML. Despite the ability of drugs to prevent the progression of the disease, pathological changes in the brain are irreversible and lead to persistent disability of patients, therefore, it is necessary to diagnose PML in the early stages of the disease.

Research Highlights

Research Highlights

Association of Progressive Multifocal Leukoencephalopathy Lesion Volume With JC Virus Polymerase Chain Reaction Results in Cerebrospinal Fluid of Natalizumab-Treated Patients With Multiple Sclerosis

The JC virus (JCV) was named after the first patient to be described with progressive multifocal leukoencephalopathy (PML), John Cunningham. Detection of JC virus DNA in cerebrospinal fluid (CSF) by polymerase chain reaction (PCR), and of specific lesions by brain magnetic resonance imaging (MRI), are both considered essential for the diagnosis of natalizumab-associated PML (NTZ-PML) in patients with multiple sclerosis. However, strict pharmacovigilance by MRI can result in detection of patients with small lesions and undetectable JCV DNA in CSF. To investigate the association of PML lesion characteristics on MRI with both qualitative and quantitative JCV PCR results in CSF of patients with NTZ-PML. This was a retrospective, cross-sectional study conducted from January 2007 to December 2014 in patients considered to have NTZ-PML based on a set of predefined criteria. Follow-up was at least 6 months. Data of patients from the Dutch-Belgian NTZ-PML cohort and patients treated at multiple medical centers in Belgium and the Netherlands and selected for research purposes were included as a convenience sample. Brain MRI scans were analyzed for PML lesion volume, location, dissemination, and signs of inflammation. Associations of the qualitative and quantitative CSF JCV PCR results with PML MRI characteristics were calculated. Of the 73 patients screened, 56 were included (37 were women). At inclusion, 9 patients (16.1%) had undetectable JCV DNA in CSF. Patients with a positive PCR had larger total PML lesion volumes than those with undetectable JCV DNA (median volume, 22.9 mL; interquartile range, 9.2-60.4 mL vs median volume, 6.7 mL; interquartile range, 4.9-14.7 mL; P = .008), and logistic regression showed that a lower PML lesion volume significantly increased the probability for undetectable JCV DNA. There was a positive correlation between PML lesion volume and JCV copy numbers (Spearman ρ, 0.32; P = .03). Progressive multifocal leukoencephalopathy lesion volume was higher in patients with PML symptoms and in patients with more widespread lesion dissemination. No association was found between PCR results and PML lesion dissemination, signs of inflammation, or PML symptoms. Smaller NTZ-PML lesions are associated with a higher likelihood of undetectable JCV DNA in CSF. This may preclude a formal diagnosis of PML and can complicate patient treatment in patients with small MRI lesions highly suggestive of PML detected early through pharmacovigilance.

No evidence of beneficial effects of plasmapheresis in natalizumab-associated PML.

To examine retrospectively the effects of plasmapheresis (PLEX) on the survival and clinical outcomes of patients with multiple sclerosis (MS) and natalizumab (NTZ)-associated progressive multifocal leukoencephalopathy (PML). The medical literature was searched for the terms natalizumab and progressive multifocal leukoencephalopathy. A total of 193 international and 34 Italian NTZ-PML cases were included. Clinical outcome was determined by comparing the patients' clinical status at PML diagnosis with status after PML resolution. The effects on survival and clinical outcome of PLEX, sex, age, country, pre-PML Expanded Disability Status Scale score, NTZ infusion number, prior immunosuppressant exposure, PML symptoms, PML lesion location at diagnosis, CSF JC virus status and copies, additional PML treatments and steroids, and PML immune reconstitution inflammatory syndrome (IRIS) development were investigated with both univariate and multivariate analyses. A total of 219 NTZ-PML cases were analyzed, and 184 (84%) underwent PLEX, which did not reduce the mortality risk or the likelihood of poor vs favorable outcomes. Country was predictive of mortality and poor outcome, while PML-IRIS development was predictive of poor outcome. PLEX did not improve the survival or clinical outcomes of Italian or international patients with MS and NTZ-PML, suggesting that this treatment should be performed cautiously in the future. This study provides Class III evidence that for patients with NTZ-PML, PLEX does not improve survival. The study lacks the statistical precision to exclude an important benefit or harm of PLEX.

Assessing understanding of individual risk and symptoms of progressive multifocal leukoencephalopathy in patients prescribed natalizumab for multiple sclerosis.

Natalizumab, a monoclonal antibody directed against α4 integrin, is a highly efficacious treatment commonly used in relapsing remitting multiple sclerosis. Natalizumab is associated with the potentially fatal, rare, demyelinating, opportunistic brain infection, progressive multifocal leukoencephalopathy (PML). Prognosis and disability from PML are determined by early diagnosis. Written tools are mandated in Australia and other prescribing countries with the aim to help patients understand the risks associated with treatment and ensure familiarity with the early symptoms of PML. We aimed to assess if these tools achieve such an outcome. A cross-sectional survey was conducted using a convenience sample of multiple sclerosis patients prescribed natalizumab presenting to the infusion centre at a major tertiary hospital. Patients were offered a multi-choice questionnaire to assess their knowledge on the treatment risks and surveillance requirements of their therapy. Three specific questions were highlighted by the researchers as crucial to patient understanding of PML and defined as basic knowledge. A total of 48 patients in our hospital was prescribed natalizumab; 37 responded. A total of 16 (43.2%) patients answered all three basic knowledge questions correctly. There was no difference in the ability to answer these questions based on length of treatment or co-ownership knowledge between patients with base knowledge and without. Natalizumab is associated with an increased risk of PML. Early detection and treatment of PML results in improved patient outcomes. Patient knowledge and co-partnership in the utilisation of PML risk tools is relevant in ensuring early detection. Our findings question the ability of currently sanctioned tools to inform patients of basic knowledge of PML and their risk of developing PML. A future study with a repetitive education approach and repeating the questionnaire at multiple time points would be of interest.

Progressive multifocal leukoencephalopathy: A review

Progressive Multifocal Leukoencephalopathy is a demyelinating disease of the Central Nervous System characterized by widespread lesions due to infection of oligodendrocytes by JC (John Cunningham) virus. Neurological manifestations of JCV induced tissue damage include the classic triad of presenting symptoms of PML. These are visual, motor, and cognitive impairments. In 40% of the initial symptoms, Hemianopsia or the loss of vision in the bisection of the visual field is the most common. In greater than 50% of the cases, severe muscle weakness progressing into hemiparesis or hemiplegia is present. The diagnosis of PML is most appropriately done by brain imaging technique. A classic triad of demyelination, bizarre astrocytes, and oligodendroglial nuclear inclusions include the histopathology of PML. Both serum and CSF should be examined for antibodies against JCV before going for a Brain biopsy. All treatments are exploratory in progressive multifocal Leukoencephalopathy (PML). In PML patients with undetectable plasma HIV, Intensive treatment with 4 classes of antiretroviral drugs, including enfuvirtide, has been reported as delivering a possible survival benefit. Treatment guidelines consider the use of corticosteroids justified in this setting. Further approaches to the isolation of virus and the immunization against the virus may arrest the progression of PML and its deadly complications.

Predictors and characteristics of seizures in survivors of progressive multifocal leukoencephalopathy.

This study aims to determine the risk factors for epileptogenesis and characteristics of seizures in patients with progressive multifocal leukoencephalopathy (PML) who survive more than 1year from onset of neurological symptoms (PML survivors). We reviewed clinical data including seizure history and MR imaging studies from PML survivors evaluated at our institution between 1997 and 2014. PML progressors who passed away within 1year and patients with a history of seizures prior to PML diagnosis were excluded from the analysis. Of 64 PML survivors, 28 (44%) developed seizures. The median time from the onset of PML symptoms to the first seizure was 5.4months (range 0-159) and 64% of patients with seizures had them within the first year. The presence of juxtacortical PML lesions was associated with a relative risk of seizures of 3.5 (p < 0.02; 95% confidence interval (CI) 1.3-9.4) in multivariate analyses. Of all seizure types, 86% were focal and 60% most likely originated from the frontal lobes. Among seizure patients, 89% required treatment, including one (54%), two (25%), or three (10.5%) antiepileptic drugs. Seizures are a frequent complication in PML and can develop throughout the entire course of the disease. However, late onset seizures did not signify PML relapse. Seizures may require treatment with multiple antiepileptic medications and are a significant co-morbidity in PML.

Monitoring the John Cunningham virus throughout natalizumab treatment in multiple sclerosis patients.

Progressive multifocal leukoencephalopathy (PML) cases have arisen amongst multiple sclerosis patients treated with natalizumab. Our objective was to gain a better understanding of the mechanisms that underlie the John Cunningham virus (JCV) infection which causes PML. A study was made of (i) the quarterly JCV DNA levels in peripheral blood mononuclear cells (PBMCs), serum and urine samples in 100 multiple sclerosis patients during their natalizumab treatment (3-39 months), (ii) the association between human leukocyte antigen (HLA) class II and the previous viral detection and (iii) the identification of the JCV variants in those patients suspected of having PML. (i) JCV DNA in PBMCs and/or serum was detected in 23% of our cohort. Patients with an intermittent JCV excretion in urine had a significant increase of the viral load and prevalence in this compartment during natalizumab treatment. (ii) The frequency of the DRB1*07/DQA1*02:01/DQB1*02:02 haplotype tended to be higher in patients with detectable versus undetectable JCV DNA in PBMCs (P(corrected) = 0.108). (iii) The variants in PBMCs and serum of the non-PML patient matched the archetype. In the patient with non-fatal PML, the archetype and the same neurotropic variant in PBMCs, serum and cerebrospinal fluid was identified at the time PML was diagnosed, whereas in the patient with a worse PML prognosis, four neurotropic variants in the three previous compartments were found by the PML diagnosis. The detection of the neurotropic variant in blood during natalizumab treatment could be critical in the prevention of the development of severe PML, since this variant appears simultaneously with the clinical symptoms of PML and mutates quickly.

PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY AND OTHER NEUROLOGICAL SYMPTOMS OF ACTIVE JC VIRUS

JC virus can exist in latent state in human bodies of many people. It can be activated in subjects with immunodeficiency and manifest with progressive multifocal leukoencephalopathy (PML) and some other neurological symptoms of central nervous system disorder. Most frequently people with AIDS suffer from JC virus. Reactivation of JC virus has recently been seen on immunosuppressive therapy. The article presents literature review of clinical and neuroimaging symptoms of PML associated with high-active HIV antiretrovirus therapy and natalizumab therapy of multiple sclerosis. The article also presents the inflammatory syndrome of immunity recovery.

Rituximab-Associated Progressive Multifocal Leukoencephalopathy (PML) in HIV-Negative Patients: An Updated Report of 231 Confirmed Cases from the Southern Network on Adverse Reactions (SONAR)/Washington University Collaboration (2000-2012)

Background: PML is an often fatal demyelinating disease of the brain due to reactivation of latent JC polyoma virus. Rituximab is an anti-CD20 monoclonal antibody associated with PML, as outlined briefly in a revised Black Box warning in 2007 and a series of Dear Healthcare Professional Letters sent by the manufacturer between 2006 and 2008. In 2009, we described 57 HIV-negative patients who developed PML after rituximab treatment [Blood. 2009; 113(20):4834–40]. Since then, the use of rituximab has continued to increase as has awareness of this association.Methods: A Freedom of Information (FOI) Act request was submitted to the U.S. Food and Drug Administration (FDA) for reports of PML cases occurring in rituximab-treated patients. These reports were obtained from the FDA in September 2013, and by definition of the FOI request, were at least 6 months old at the time obtained. Of the 483 total reports received, 173 duplicate cases were identified based on similar dates, ages, and other clinical information, resulting in 310 unique cases. An additional 14 cases were added from our 2009 publication that were not included in the original 310 cases, totaling 324 unique cases. Our case definition included HIV-negative patients in whom rituximab was administered prior to the onset of PML symptoms, with PML confirmed via brain biopsy, autopsy, or having JC virus in cerebrospinal fluid (CSF) plus brain MRI findings of PML.Results: Of the 324 unique cases, there were 231 confirmed cases of rituximab-associated PML in HIV-negative patients, from 23 countries. The majority of excluded cases lacked the necessary details in the reports to confirm the diagnosis of PML. Among the confirmed cases, case mortality rate was 89.1%. PML diagnosis was made by brain MRI AND positive JC virus CSF PCR (67.5%), brain biopsy (34.6%), or autopsy (7.8%). Indications for rituximab use included non-Hodgkin lymphoma (58.8%), chronic lymphocytic leukemia (28.4%), rheumatoid arthritis (3.1%), systemic lupus erythematosus (2.6%), autoimmune hemolytic anemia/idiopathic thrombocytopenic purpura (2.6%), and other rheumatologic conditions (3.5%). The non-Hodgkin lymphomas were subdivided into follicular (13.5%), diffuse large B-cell (9.2%), unspecified non-Hodgkin (22.7%), mantle cell (7%), Waldenstrom (4.4%), and marginal zone (1.7%). Median age was 64.5 years (range 19-90), 53% female and 47% male, with 25 patients (10.8%) having undergone prior transplantation (12 autologous stem cell, 8 allogeneic stem cell, and 5 solid organ). The median number of rituximab doses received was 6 (range 1-24), with a median of 15 months (range 0.5-128) from first dose of rituximab to PML diagnosis, and median of 4 months (range 0-65) from last rituximab dose to PML. The median time from PML diagnosis to death was 2 months (range 0-14). It is noteworthy that of the cases diagnosed by brain biopsy or autopsy, 17 had a negative JC virus CSF PCR, and of the cases diagnosed with a positive JC virus CSF PCR, 8 had at least one negative test before the diagnosis was made. Less than 10 cases per year were diagnosed until 2006 when there were 22, peaking at 40 in 2010 (figure). [Display omitted] Conclusions: PML continues to be increasingly reported by clinicians who administer rituximab with or without concomitant chemotherapy. The temporal increase in the number of reports suggests that either the incidence may be higher than initially thought or increased awareness has led to more reporting. Furthermore, the lower number of reports in 2012 likely illustrates the delay between incident cases, reporting, and availability through FOI requests. Our findings highlight the importance of detailed adverse event reporting (as is characteristic of SONAR) to enhance clinician awareness of rare but serious toxicities, as well as the need for faster public availability of adverse event reports. DisclosuresOff Label Use: Rituximab is used for a variety of indications. Our abstract describes the indications with percentages that rituximab was used from our analysis. These FDA-approved indications include chronic lymphocytic leukemia, lymphomas as listed, and rheumatoid arthritis. Indications listed that are not FDA-approved (the minority) include systemic lupus erythematosus, autoimmune hemolytic anemia/idiopathic thrombocytopenic purpura, and other rheumatologic conditions.. Carson:Genentech: Consultancy, Honoraria, Speakers Bureau.

Clinical and paraclinical findings in natalizumab-associated infratentorial progressive multifocal leukoencephalopathy patients: Table 1

Natalizumab (NAT)-treated relapsing remitting multiple sclerosis (RRMS) patients have a marked progressive multifocal leukoencephalopathy (PML) risk, with an overall incidence of 3.4 per 1000 NAT treated patients (95%− CI 3.08 to 3.74).1 In HIV-positive PML patients a supratentorial manifestation occurred in 93.8%. An infratentorial PML manifestation is less frequent, occurring in 11–58.3% of the HIV-positive PML patients.2 ,3 Within the infratentorial brain structures, the pons is most commonly affected.2 Irie et al reported a infratentorial PML manifestation in one patient with renal failure. They found an overall survival of ≤4 months after onset of infratentorial PML symptoms.4 Up to now no clinical studies regarding NAT-PML with a predominant infratentorial manifestation have been published. Our study aimed to investigate differences in clinical data and disease course between NAT-PML patients with or without initial infratentorial involvement. NAT-PML patients treated in two German university hospitals (Bochum n=21, Hannover n=3,) until 1 November 2013 were included in this retrospective study (ethic committees: Bochum 4566–13, Hannover: 2100−2013). Treatment of NAT-PML was standardised including plasma exchange, mirtazapine and mefloquine treatment. Patients were followed for 14.6±12.4 months (mean±SD), basic characteristics and clinical data were collected by medical records. Extended Disability Status Scale (EDSS) and Karnofsky Index (KI) were performed at onset, after the immune reconstitution inflammatory syndrome (IRIS), and after 6 months post-NAT-PML diagnosis, 1,5-Tesla MRI scans were obtained. Compared with our preceding work,5 we focused on the speciality of infratentorial PML manifestations and included a larger patient population. Statistical analysis was performed using SPSS …

Progressive multifocal leukoencephalopathy in transplant recipients

Transplant recipients are at risk of developing progressive multifocal leukoencephalopathy (PML), a rare demyelinating disorder caused by oligodendrocyte destruction by JC virus. Reports of PML following transplantation were found using PubMed Entrez (1958-July 2010). A multicenter, retrospective cohort study also identified all cases of PML among transplant recipients diagnosed at Mayo Clinic, Johns Hopkins University, Washington University, and Amsterdam Academic Medical Center. At 1 institution, the incidence of posttransplantation PML was calculated. A total of 69 cases (44 solid organ, 25 bone marrow) of posttransplantation PML were found including 15 from the 4 medical centers and another 54 from the literature. The median time to development of first symptoms of PML following transplantation was longer in solid organ vs bone marrow recipients (27 vs 11 months, p = 0.0005, range of <1 to >240). Median survival following symptom onset was 6.4 months in solid organ vs 19.5 months in bone marrow recipients (p = 0.068). Case fatality was 84% (95% confidence interval [CI], 70.3-92.4%) and survival beyond 1 year was 55.7% (95% CI, 41.2-67.2%). The incidence of PML among heart and/or lung transplant recipients at 1 institution was 1.24 per 1,000 posttransplantation person-years (95% CI, 0.25-3.61). No clear association was found with any 1 immunosuppressant agent. No treatment provided demonstrable therapeutic benefit. The risk of PML exists throughout the posttransplantation period. Bone marrow recipients survive longer than solid organ recipients but may have a lower median time to first symptoms of PML. Posttransplantation PML has a higher case fatality and may have a higher incidence than reported in human immunodeficiency virus (HIV) patients on highly-active antiretroviral therapy (HAART) or multiple sclerosis patients treated with natalizumab.

Unmasking of PML by HAART: Unusual clinical features and the role of IRIS

For patients with HIV/AIDS, highly active antiretroviral therapy (HAART) is currently the only effective therapy for progressive multifocal leukoencephalopathy (PML), a viral-induced demyelinating disease caused by polyomavirus JC. Immune reconstitution inflammatory syndrome (IRIS) following initiation of HAART can cause paradoxical clinical deterioration in patients with established PML. Because the onset of PML follows soon after initiation of HAART in some cases (unmasking), we investigated the role IRIS plays in unmasked PML. We reviewed records of 20 PML cases seen from 1997–2006 at the UCSD HIV primary care clinic. Eight cases presented with PML symptoms within 6 months of initiating HAART (referred to hereafter as unmasked PML), six patients were diagnosed with PML before initiating HAART, and six were diagnosed more than 6 months after starting HAART. Patients with unmasked PML constituted 40% of our series, had relatively long survival, and commonly (50%) had lesions exclusively in the posterior fossa, a localization not previously reported with such a high prevalence. Only 3 of the 8 patients with unmasked PML had IRIS reactions as evidenced by contrast enhancement around lesions on MRI, suggesting that IRIS is not necessary for the pathogenesis of this syndrome.

Stronger association of drug-induced progressive multifocal leukoencephalopathy (PML) with biological immunomodulating agents

The aim of the present study was to collect and compare cases of drug-induced PML in order to contribute to the debate about the role of the underlying diseases and/or drug immunosuppression in PML occurrence. We searched for drug-induced PML cases in two international spontaneous adverse drug reaction (ADR) report databases, FDA-AERS and WHO-VigiBase. From MEDLINE, we retrieved case reports and case series containing the MESH term "leukoencephalopathy, progressive multifocal/chemically induced". In order to assess the PML-drug relationship, we analysed drug-reaction pairs in terms of the patients' underlying diseases and co-suspected drugs. Overall, 214 cases in FDA-AERS, 118 in WHO-VigiBase and 140 in MEDLINE were collected. Therapeutic groups more frequently involved in PML cases were monoclonal antibodies (MAbs), conventional immunosuppressive drugs and anti-HIV drugs. The most frequent underlying diseases were lymphoproliferative diseases (28%), autoimmune disorders (20%) and transplants (10%). MAbs were more often reported in cases where they were the only suspected drugs, whereas for the other therapeutic groups, concomitant drugs were reported. We found a strong relationship between PML and MAbs, especially when used in autoimmune diseases. PML is becoming a crucial issue of MAbs, since they can cause severe ADRs through the imbalance of the immune system. Based on these results, patients treated with MAbs should be carefully monitored for early signs and symptoms of PML.