Hiv-Related Progressive Multifocal Leukoencephalopathy: A Case Report

Case presentation: A 40-year-old female presented with a one-week history of uncoordinated movements and difficulty walking, accompanied by brief episodes of vertigo. She was diagnosed with HIV approximately 3 months before and since then was regularly on antiretroviral therapy (TDF + 3TC + DTG) and sulfamethoxazole-trimethoprim for neurotoxoplasmosis treatment. On neurological examination, she exhibited debilitating imbalance while standing, significant ataxia on finger-to-nose and heel-to-shin tests bilaterally and bilateral horizontal nystagmus. Laboratory tests showed a viral load of 600 copies/ml and a CD4 cell count of 113 cells/ml. Brain magnetic resonance imaging (MRI) revealed a lesion hyperintense on T2 and FLAIR sequences in the left cerebellar hemisphere, sparing the dentate nucleus, suggestive of the "shrimp sign" described in cases of progressive multifocal leukoencephalopathy (PML) (Figure 1A). Initial cerebrospinal fluid (CSF) analysis was normal, including PCR for John Cunningham (JC) virus and, therefore, no specific treatment was started, and the patient remained hospitalized for follow-up. One month after admission, a new brain MRI was performed, now showing bilateral cerebellar lesions with the "shrimp sign" appearance (Figure 1B), and a new CSF PCR for JC virus was requested and returned positive, thus establishing the diagnosis of PML. Discussion: Cerebellar ataxia in HIV patients can have metabolic, infectious, vascular, or autoimmune etiologies, and may or may not be related to the presence of the retrovirus itself. PML is an opportunistic demyelinating disease of the central nervous system, associated with the presence of the JC polyomavirus typically in patients with CD4 counts < 200 cells/ml, and can manifest as an ataxic syndrome due to asymmetric involvement of the cerebellum. The shrimp sign on brain MRI has high sensitivity and specificity for the diagnosis of cerebellar PML. The diagnosis of PML without histopathological findings is based on a combination of typical clinical and neuroimaging findings associated with JC virus positivity in the CSF. When these three criteria are met, the diagnosis is definitive, according to AAN criteria. The treatment of HIV-associated PLM typically involves improving the patients immune status with the use of antiretroviral drugs, although the neurological deficits observed are usually irreversible. Final comments: New-onset cerebellar ataxia in HIV patients can be an uncommon clinical manifestation of PML and should be considered among the differential diagnoses, especially in patients with low CD4 cell counts. Despite the improved survival of these patients with the initiation of effective antiretroviral therapy, this condition remains serious and usually has a poor neurological prognosis.

Finger pointing to JC virus: a tale of two indexes.

Progressive multifocal leukoencephalopathy (PML) is a rare, demyelinating disease of the central nervous system that usually leads to death or severe disability. Affected patients present with signs and symptoms including impaired cognition, visual disturbances, hemiparesis, altered mental state and behavioural changes. PML is caused by activation of the John Cunningham (JC) virus. JC virus resides in latent form in up to 80 percent of adults. Reactivation of JC virus occurs in immunocompromised patients. The factors leading to activation of the latent infection are not fully understood. The diagnosis of PML is established based on a detailed medical history, physical examination, suggestive MRI findings and the presence of the JC virus detected in the cerebrospinal fluid by PCR. PML has been reported in the published literature in HIV-positive patients, as well as in patients receiving immunosuppressive agents because of organ transplantation, cancer or autoimmune diseases. PML has been reported in patients receiving classical immunosuppressive drugs or biologics or both [1]. There are no known interventions that can prevent or treat PML successfully. Recently, two confirmed cases of PML have been reported in US patients receiving efalizumab (Raptiva®) for chronic plaque psoriasis [2]. One male patient (age 70) and one female patient (age 73) had received efalizumab for 4 and 3.8 years, respectively. These are the first confirmed cases of PML in psoriasis patients receiving immunosuppressive therapy. Today, the global exposure of patients on efalizumab is 47,000 patient-years. Until more information is available and further guidance is received from the health authorities, a group of independent expert dermatologists advise to strictly follow the Summary of Product Characteristics of efalizumab [3]. Dermatologists should carefully weigh risks and benefits in patients during long-term therapy with efalizumab and particularly in those of advanced age or with a history of immunosuppressive therapy. In patients receiving any immunosuppressive therapy, dermatologists should be vigilant for signs and symptoms suggestive of PML. Suspicious cases should be referred to a neurologist.

Progressive multifocal leukoencephalopathy (PML) is a rapidly progressive degenerative demyelinating disease that results from infection with JC virus. PML usually occurs in an immunocompromised individual, putatively attributable to reactivation of a latent JC virus. In childhood PML has been reported in individuals with acquired immunodeficiency syndrome (AIDS),1–3 Wiskott–Aldrich syndrome,4 and inherited immunodeficiencies.5,,6We report here a 15-year-old boy with generalized morphea, a form of limited cutaneous sclerodema, and secondary amyloidosis who developed PML. The rapid onset of his neurologic manifestations and the initial neuroimaging studies suggested acute disseminated encephalomyelitis (ADEM), and a brain biopsy was needed for the diagnosis of PML. A 15-year-old boy with scleroderma and amyloidosis was admitted for progressive ataxia, dysarthria, and weakness. His medical history was notable for generalized morphea confirmed by a skin biopsy at 3 years of age. He had severe cutaneous involvement and finger and toe contractures attributable to skin and soft tissue involvement. He was treated with prednisone andD-penicillamine for several years. All autoantibodies were negative, and immunologic work-up revealed normal complement and immunoglobulin levels but a low absolute T-cell count of 533 cells/μL. There was no evidence of active arthritis or recurrent infections. Two years before admission, he was diagnosed with secondary amyloidosis with serum amyloid A protein by liver biopsy. A concomitant skin biopsy showed no evidence of amyloid deposition and continued to be consistent with morphea. Proteinuria was noted. Prednisone was stopped, and chlorambucil (4 mg per day) was started. He responded well to the chlorambucil over the next several months with significant regression of amyloidosis-related clinical findings and marked dermatologic improvement. He was maintained on chlorambucil only. However, 2 months before admission the dosage had to be decreased from 4 mg to 3 mg daily because of leukopenia with a white …

IL-7 immunotherapy for progressive multifocal leukoencephalopathy in a patient with already controlled HIV-1 infection on antiretroviral therapy.

Progressive multifocal leukoencephalopathy is an AIDS defining disease often arising in HIV patients with low CD4 T cell count, and rarely among those with more than 500 CD4 T cell/mm 3 . Definite diagnosis requires JC Virus (JCV) isolation in cerebrospinal fluid (CSF) or in brain tissue. JCV PCR sensitivity in highly active antiretroviral therapy (HAART) era is lower, making progressive multifocal leukoencephalopathy (PML) definite diagnosis difficult. A 48-year-old woman was diagnosed with HIV1 in 1998, never having had any AIDS-defining illness. Combined antiretroviral therapy was started in 2004. In January 2009 she presented a tandem gait and gait ataxia. Her HIV viral load was undetectable and the CD4 T cell count was of 533/mm 3 . Brain CT scan was normal. In the following months a bilateral cerebellar syndrome installed and brain MRI was done showing asymmetrical demyelinating lesions. Normal cerebrospinal fluid (CSF) findings other than mononuclear pleocytosis and a negative JCV PCR were documented. PML was suspected, combined antiretroviral therapy (cARV) was altered, and cidofovir and mirtazapine were prescribed, associated with physiotherapy. She was clinically stable for some months. Almost one year later her neurological state got worse, CD4 T cell count was of 478/mm 3 , brain lesions progressed, and finally, JCV PCR became positive (5th determination). PML definite diagnosis was made. The patient died in June 2010 due to PML progression. Sensitivity of JCV PCR in CSF lowers under HAART with high CD4 T cell count, making definite PML diagnosis difficult even when a high grade of suspicion exists, based on clinical presentation and magnetic resonance imaging (MRI) findings. Differential diagnosis of demyelinating diseases should be considered, and HIV-leukoencephalitis should be taken in consideration when HIV replication exists in the brain. PML may arise in a patient under cARV and good immunological status. Treatment should not be delayed when a probable diagnosis exists even if CD4 T cell count is above 500/mm 3 . Repeated lumbar puncture with JCV determinations should be done in the advent of new/worsen neurological symptoms and evidence of demyelination showed in MRI. Sensitivity of JCV PCR increases with lower CD4 T cell count. doi:10.4021/jmc78w

First Estimates of Incidence of Progressive Multifocal Leukoencephalopathy Developing Among 10,459 Non-HIV Lymphoma VA Patients Who Receive Rituximab: Results From the Veterans Administration Database (1999–2012).

JC and BK polyomavirus-like particles as targets of innate and adaptive humoral immunity

Rituximab postprogressive multifocal leukoencephalopathy: a Feasible therapeutic option in selected cases.

Progressive multifocal leukoencephalopathy (PML), a rare neurological disease, has been sporadically reported in persons infected with human immunodeficiency virus (HIV), the causative agent of acquired immune deficiency syndrome (AIDS). From January 1981 through February 1989, in San Francisco, we identified 94 HIV-infected persons with PML, of whom 48 (51%) were pathologically confirmed (as required for AIDS case reporting). These 48 patients were significantly older when diagnosed with AIDS (20% older than 50 years) than patients with AIDS without PML. The remaining 46 (49%) patients, diagnosed clinically and by neuroimaging, did not differ significantly from definitive patients in demographic or survival characteristics after PML diagnosis. We detected antibodies to JC virus, the causative agent of PML, in 9 of 14 (64%) AIDS-related patients with PML, and in 9 of 14 (64%) matched control subjects, suggesting that determination of JC virus antibody status before AIDS diagnosis does not reliably indicate which patients will contract PML. Our study shows that the proportion of patients with AIDS who contracted PML remained stable between 1981 and 1988, but increased in the first 2 months of 1989. Our findings further indicate that PML in HIV-infected patients may be underestimated by as much as 50%.

Loss of T cell control during persistent polyomavirus infection, in the setting of a limited antiviral antibody response, facilitates emergence of antibody-escape viruses carrying the potential for neurovirulence.

PML therapy: “It's Déjà vu all over again”

Spontaneous recovery from progressive multifocal leukoencephalopathy in a patient with non-active sarcoidosis

To determine the clinical value of JC virus (JCV) detection in various anatomic compartments for the diagnosis of progressive multifocal leukoencephalopathy (PML). CSF, peripheral blood mononuclear cells (PBMC), plasma, and urine samples were evaluated from HIV-infected and uninfected individuals. JCV DNA was detected by PCR and was quantified using a competitive PCR ELISA. JCV DNA was detected in one-third of the urine samples, regardless of HIV serostatus or clinical evidence of PML. JCV DNA was detected in five of eight PBMC and three of seven plasma samples of HIV-positive PML patients, in 13 of 103 PBMC and 7 of 32 plasma samples of HIV-positive persons without PML, but in 0 of 18 PBMC and 0 of 13 plasma samples of HIV-negative control subjects. There was no correlation between the presence of JCV DNA in the PBMC and plasma, but the detection of JCV in either compartment was associated with low CD4+ lymphocyte counts. JCV DNA was not detected in the CSF of 27 of 27 HIV-negative persons and 64 of 65 HIV-positive persons without PML, but was found in the CSF of three of three HIV-negative immunosuppressed individuals and 10 of 11 HIV-positive individuals with clinical and radiologic evidence of PML, confirmed by biopsy in four of four tested patients. PBMC harbored 10 to 90 JCV copies/microg DNA, and the CSF of the PML patients contained 3.65 x 10(4) to 2.04 x 10(5) JCV copies/mL CSF. JCV viruria was found as frequently in HIV-positive individuals as in control subjects, suggesting that its detection has no clinical value. JCV detection in the blood correlates with immunosuppression and not with PML. The presence of JCV in the CSF is highly sensitive and specific for PML, and a high CSF JC viral load was associated with poor clinical outcome in patients receiving antiretroviral therapy. JCV quantification in the CSF constitutes a potentially important tool for monitoring clinical PML treatment trials.

PML is a progressive and mostly fatal demyelinating disease caused by JC virus infection and destruction of infected oligodendrocytes in multiple brain foci of susceptible individuals. While JC virus is highly prevalent in the human population, PML is a rare disease that exclusively afflicts only a small percentage of immunocompromised individuals including those affected by HIV (AIDS) or immunosuppressive drugs. Viral- and/or host-specific factors, and not simply immune status, must be at play to account for the very large discrepancy between viral prevalence and low disease incidence. Here, we show that several amino acids on the surface of the JC virus capsid protein VP1 display accelerated evolution in viral sequences isolated from PML patients but not in sequences isolated from healthy subjects. We provide strong evidence that at least some of these mutations are involved in binding of sialic acid, a known receptor for the JC virus. Using statistical methods of molecular evolution, we performed a comprehensive analysis of JC virus VP1 sequences isolated from 55 PML patients and 253 sequences isolated from the urine of healthy individuals and found that a subset of amino acids found exclusively among PML VP1 sequences is acquired via adaptive evolution. By modeling of the 3-D structure of the JC virus capsid, we showed that these residues are located within the sialic acid binding site, a JC virus receptor for cell infection. Finally, we go on to demonstrate the involvement of some of these sites in receptor binding by demonstrating a profound reduction in hemagglutination properties of viral-like particles made of the VP1 protein carrying these mutations. Collectively, these results suggest that a more virulent PML causing phenotype of JC virus is acquired via adaptive evolution that changes viral specificity for its cellular receptor(s).