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The COVID-19 pandemic posed unprecedented challenges to healthcare systems worldwide, particularly in managing critically ill patients requiring mechanical ventilation early in the pandemic. Surging patient volumes strained hospital resources and complicated the implementation of standard-of-care intensive care unit (ICU) practices, including sedation management. The objective of this study was to evaluate the impact of an evidence-based ICU sedation bundle during the early COVID-19 pandemic. The bundle was designed by a multi-disciplinary collaborative to reinforce best clinical practices related to ICU sedation. The bundle was implemented prospectively with retrospective analysis of electronic medical record data. The setting was the ICUs of a single-center tertiary hospital. The patients were the ICU patients requiring mechanical ventilation for confirmed COVID-19 between March and June 2020. A learning health collaborative developed a sedation bundle encouraging goal-directed sedation and use of adjunctive strategies to avoid excessive sedative administration. Implementation strategies included structured in-service training, audit and feedback, and continuous improvement. Sedative utilization and clinical outcomes were compared between patients admitted before and after the sedation bundle implementation. Quasi-experimental interrupted time-series analyses of pre and post intervention sedative utilization, hospital length of stay, and number of days free of delirium, coma, or death in 21 days (as a quantitative measure of encephalopathy burden). The analysis used the time duration between start of the COVID-19 wave and ICU admission to identify a “breakpoint” indicating a change in observed trends. A total of 183 patients (age 59.0 ± 15.9 years) were included, with 83 (45%) admitted before the intervention began. Benzodiazepine utilization increased for patients admitted after the bundle implementation, while agents intended to reduce benzodiazepine use showed no greater utilization. No “breakpoint” was identified to suggest the bundle impacted any endpoint measure. However, increasing time between COVID-19 wave start and ICU admission was associated with fewer delirium, coma, and death-free days (β=  − 0.044 [95% CI − 0.085, − 0.003] days/wave day); more days of benzodiazepine infusion (β= 0.056 [95% CI 0.025, 0.088] days/wave day); and a higher maximum benzodiazepine infusion rate (β= 0.079 [95% CI 0.037, 0.120] mg/h/wave day). The evidence-based practice bundle did not significantly alter sedation utilization patterns during the first COVID-19 wave. Sedation practices deteriorated and encephalopathy burden increased over time, highlighting that strategies to reinforce clinical practices may be hindered under conditions of extreme healthcare system strain.

Background Few studies exist to describe the characteristics of symptomatic syphilitic meningitis, particularly in sub-Saharan Africa, despite a global resurgence.Methods We conducted a retrospective analysis of a cohort of adults with meningitis presenting to Zambia’s largest referral hospital between April 2014 and December 2017. Individuals with pyogenic bacterial and cryptococcal meningitis were excluded from this cohort. We calculated the prevalence of syphilitic meningitis in the cohort and described the demographic, clinical and laboratory characteristics and outcomes.Results Of 512 participants, 273 were male, mean age was 37 ± 11 years and 84% were people living with HIV. The prevalence of syphilitic meningitis was 5% with in-hospital and 1-year mortality of 17% and 53%, respectively. Participants with syphilitic meningitis had lower Glasgow Coma Scores than those with other forms of meningitis. Among people living with HIV, those with syphilitic meningitis were less likely to have meningismus and had higher CSF white cell counts.Conclusions Syphilitic meningitis was found in 5% of Zambian adults presenting with non-pyogenic bacterial meningitis and non-cryptococcal meningitis, and one-year mortality was high. A high degree of clinical suspicion for syphilitic meningitis in all individuals with meningitis in Zambia is recommended, especially in people living with HIV.

The diaphragm, the principle muscle of inspiration, is an under‐recognized contributor to respiratory disease. Dysfunction of the diaphragm can occur secondary to lung disease, prolonged ventilation, phrenic nerve injury, neuromuscular disease, and central nervous system pathology. In light of the global pandemic of coronavirus disease 2019 (COVID‐19), there has been growing interest in the utility of ultrasound for evaluation of respiratory symptoms including lung and diaphragm sonography. Diaphragm ultrasound can be utilized to diagnose diaphragm dysfunction, assess severity of dysfunction, and monitor disease progression. This article reviews diaphragm and phrenic nerve ultrasound and describes clinical applications in the context of COVID‐19.

Background: Persistent viral RNA shedding of SARS-CoV-2 following COVID-19 has increasingly been recognized, with limited understanding of its implications on outcomes in hospitalized COVID-19 patients. Methods: We retrospectively assessed for persistent viral shedding across Northwestern Medicine Healthcare (NMHC) patients between March and August 2020. We assessed for predictors of persistent viral shedding, in-hospital delirium, and six-month mortality using binary logistic regression. Results: Of the 2,518 hospitalized patients with an RT-PCR-confirmed diagnosis of COVID-19, 959 underwent repeat SARS-CoV-2 RT-PCR at least fourteen days from initial positive testing. Of those, 405 (42.2%) patients were found to have persistent viral shedding. Persistent viral shedding was associated with male sex, increased BMI, diabetes mellitus, chronic kidney disease, and exposure to corticosteroids during initial COVID-19 hospitalization. Persistent viral shedding was independently associated with incidence of in-hospital delirium after adjusting for factors including severity of respiratory dysfunction (OR 2.45; 95% CI 1.75, 3.45). Even after adjusting for age, severity of respiratory dysfunction, and occurrence of in-hospital delirium, persistent viral shedding remained significantly associated with increased six-month mortality (OR 2.43; 95% CI 1.42, 4.29). Conclusions: Persistent viral shedding occurs frequently in hospitalized COVID-19 patients and is associated with in-hospital delirium and increased six-month mortality.

Acute-care hospital reencounters (ACHEs)—encompassing emergency department visits, observation stays, and hospital readmissions—following COVID-19 hospitalization may exacerbate health care system strain and impair recovery from illness. We sought to characterize these reencounters and factors associated with reencounters. We identified the first consecutive 509 patients hospitalized for COVID-19 within an IL hospital network, and examined ACHEs, experienced within 30 days and 4 months of index hospitalization. We identified independent predictors of reencounter using binary logistic regression. Of 509 patients, 466 (91.6%) were discharged alive from index COVID-19 hospitalization. Within 30 days and 4 months, 12.4% and 21.5% of patients, respectively, experienced ACHEs. The median time to first ACHE was 24.2 (IQR 6.5, 55) days. COVID-19 symptom exacerbation was the leading reason for early ACHE (44.8%). Reencounters, both within 30 days and 4 months, were associated with a history of a neurological disorder before COVID-19 (OR 2.78 [95% CI 1.53, 5.03] and OR 2.75 [95% CI 1.67, 4.53], respectively). Older patients and those with diabetes mellitus, chronic obstructive pulmonary disease, or organ transplantation tended towards more frequent ACHEs. Steroid treatment during COVID-19 hospitalization demonstrated reduced odds of 30-day reencounter (OR 0.31 [95% CI 0.091, 0.79]). Forty-nine patients had repeat SARS-CoV-2 nasopharyngeal testing during a reencounter; twelve (24.5%) patients had positive reencounter tests and experienced more frequent reencounters than those testing negative. COVID-19 symptom exacerbation is a leading cause of early ACHE after COVID-19 hospitalization, and steroid use during index hospitalization may reduce early reencounters. Neurologic illness before COVID-19 predicts ACHEs.

Peripheral nerve imaging aids diagnosis and may guide management in patients with coronavirus disease 2019 with neuromuscular symptoms arising from the infectious disease, hospitalization course, or secondary to a complication of treatment.

Narcolepsy is the most common neurological cause of chronic sleepiness. The discovery about 20 years ago that narcolepsy is caused by selective loss of the neurons producing orexins (also known as hypocretins) sparked great advances in the field. Here, we review the current understanding of how orexin neurons regulate sleep–wake behaviour and the consequences of the loss of orexin neurons. We also summarize the developing evidence that narcolepsy is an autoimmune disorder that may be caused by a T cell-mediated attack on the orexin neurons and explain how these new perspectives can inform better therapeutic approaches.

AbstractJC virus is the etiological agent of progressive multifocal leukoencephalopathy, a white matter demyelinating disease that mostly affects immunocompromised patients. JC virus can also infect neurons and meningeal cells and cause encephalitis, meningitis and granule cell neuronopathy. We report a patient with JC virus granule cell neuronopathy, without concomitant progressive multifocal leukoencephalopathy, presenting as inaugural acquired immune deficiency syndrome-related illness. This patient’s human immunodeficiency virus infection remained undiagnosed for several months after neurological symptoms onset. We review JC virus pathophysiology, clinical manifestations, treatment and prognosis, and emphasize the importance of considering human immunodeficiency virus infection and related opportunistic infections in the differential diagnosis of new-onset isolated cerebellar disease.

Although JC polyomavirus infection of a kidney transplant is extremely rare, this case documents JC transplant nephropathy progressing to atypical JC polymavirus encephalopathy that was difficult to diagnose, followed by alllograft nephrectomy and discontinuation leading to improvement in the patient. Supplemental digital content is available in the text.

mRNA vaccines are effective in preventing severe COVID-19, but breakthrough infections, emerging variants, and waning immunity warrant the use of boosters. Although mRNA boosters are being implemented, the extent to which pre-existing immunity influences the efficacy of boosters remains unclear. In a cohort of individuals primed with the mRNA-1273 or BNT162b2 vaccines, we report that lower antibody levels before boost are associated with higher fold-increase in antibody levels after boost, suggesting that pre-existing antibody modulates the immunogenicity of mRNA vaccines. Our studies in mice show that pre-existing antibodies accelerate the clearance of vaccine antigen via Fc-dependent mechanisms, limiting the amount of antigen available to prime B cell responses after mRNA boosters. These data demonstrate a “tug of war” between pre-existing antibody responses and de novoB cell responses following mRNA vaccination, and they suggest that transient downmodulation of antibody effector function may improve the efficacy of mRNA boosters.

To describe acute EEG findings in HIV-infected adults with new-onset seizure, assess baseline clinical characteristics associated with EEG abnormalities, and evaluate the relationship between EEG abnormalities and recurrent seizure.

To describe the clinical, neuroimaging, immunologic, and virologic characteristics of JC virus–associated granule cell neuronopathy (JCV GCN) in a natalizumab-treated patient with multiple sclerosis (MS) who developed immune reconstitution inflammatory syndrome (IRIS) after natalizumab withdrawal.

Progressive multifocal leukoencephalopathy is a rare, demyelinating disease of the central nervous system caused by JC virus. Fewer than 30 cases have been reported in HIV- and non-infected children. We report the case of a 15-year-old girl with progressive multifocal leukoencephalopathy and AIDS who presented with nystagmus, dysarthria and ataxia. Following combined antiretroviral therapy, she developed immune reconstitution inflammatory syndrome, which proved fatal.

Simian virus 40 (SV40), family Polyomaviridae, in immunocompromised macaques can cause fatal demyelinating central nervous system disease analogous to progressive multifocal leukoencephalopathy caused by John Cunningham (JC) virus in immunocompromised humans. Recently, we have demonstrated that JC virus can infect cerebellar granule cell neurons and cortical pyramidal neurons in immunosuppressed people. To examine whether SV40 neuronal infection occurs spontaneously in immunosuppressed macaques, we analyzed archival brain specimens from 20 simian immunodeficiency virus–infected rhesus with AIDS and 1 cynomolgus post-transplant selected with SV40 brain infection from archival records from 1991 to 2012. In addition to white matter SV40 distribution in classic demyelinating progressive multifocal leukoencephalopathy, some of the 21 monkeys exhibited meningeal, subpial neocortical, and periventricular virus. This distribution pattern corresponded to broader viral tropism with neuronal infection in 14 (66.7%) of 21 cases. In all 14 cases, identified neurons were positive for early SV40 transcript large T antigen, but only 4 of the 14 cases exhibited late viral transcript viral protein 1–positive neurons. SV40-infected neurons were detected in frontal, parietal, occipital, and temporal cortices, hippocampus, thalamus, and brain stem. These observations confirm that spontaneous SV40 neuronal infection occurs in immunosuppressed macaques, which parallels JC virus–neuronal infection in immunosuppressed patients. Neuronal infection may be an important aspect of both SV40 and JC virus neuropathogenesis in their respective hosts.

To establish criteria for the diagnosis of progressive multifocal leukoencephalopathy (PML).

To characterize progressive multifocal leukoencephalopathy (PML) lesions by contrast-enhanced MRI and evaluate their metabolism using proton magnetic resonance spectroscopy (1H- MRS) in the setting of immune reconstitution inflammatory syndrome (IRIS).

Nothing is more disappointing for patients than when a promising new treatment hits a roadblock because of unexpected side effects. This is what happened when natalizumab (Tysabri) was associated with a few cases of progressive multifocal leukoencephalopathy (PML) in multiple sclerosis and Crohn's disease patients, caused by the reactivation of the polyomavirus JC. These dramatic events drew PML squarely into the spotlight and generated considerable interest from the medical community, the pharmaceutical industry, financial markets, and regulatory agencies alike. This scrutiny, in turn, helped crystallize areas of consensus and expose gaps in our understanding of PML pathogenesis. Indeed, since its initial description, there has been a considerable evolution in both the epidemiology and clinical presentations of this disease, and new manifestations of central nervous system infection by polyomavirus JC have been characterized. To keep pace with this opportunistic pathogen, we are therefore forced to reexamine the foundations of our knowledge of virus–host interactions, reappraise our investigational approaches, and in short, rethink PML down to its very name. Hopefully, this crisis will be instrumental in helping us define novel avenues of research, develop predictive tests for PML in populations at risk, and challenge us to find a treatment for this deadly disease. Ann Neurol 2006; 60: 162–173

Progressive multifocal leukoencephalopathy (PML) typically affects the CNS white matter of the central nervous system. We present an human immunodeficiency virus–infected patient with polyomavirus JC infection restricted to granule cell neurons of the cerebellum and with corresponding neurological symptomatology. Magnetic resonance imaging demonstrated cerebellar atrophy without white matter lesions and stereotactic biopsy showed selective infection of the cerebellar granular cell layer, with preservation of Purkinje cells and absence of classic progressive multifocal leukoencephalopathy histopathology in underlying white matter. Evolution over 8 years was marked by symptomatic improvement corresponding to highly active antiretroviral therapy (HAART), with modest increase in CD4+T‐cell counts. We propose to call this novel syndrome JCV granule cell neuronopathy (JCV GCN). Ann Neurol 2005;57:576–580

Progressive multifocal leukoencephalopathy (PML) is a fatal demyelinating disease of the CNS of immunosuppressed individuals caused by the polyomavirus JC (JCV). In previous studies, we showed that JCV-specific cytotoxic T lymphocytes (JCV-specific CTL) were associated with a favourable outcome in patients with PML. However, these CTL had been assessed in PML survivors more than 1 year after the onset of disease and we could not determine whether this immune response was only a surrogate marker for a general recovery of the patient's immune system or a causal factor in the patient's neurological improvement. In this study, we assessed the relationship between JCV-specific CTL detected early in the course of PML and the subsequent course of disease activity. We enrolled 26 patients with possible or proven PML, including 21 HIV+ patients, less than 10 months after the onset of their neurological symptoms (3.7 ± 2.5 months, median ± interquartile range). JCV-specific CTL were detected by either 51Cr release or tetramer staining assay. Patients were then followed prospectively and the clinical course of PML was determined. At the time of their first immune evaluation, we found that 15 patients had detectable JCV-specific CTL. HIV+ patients with JCV-specific CTL had a higher CD4+ T-cell count (215 ± 103/µl) and a lower HIV viral load (144 ± 431 copies/ml) than those without JCV-specific CTL (32 ± 59/µl, P = 0.004 and 43 100 ± 54 778 copies/ml, P = 0.01). Thirteen of these 15 patients with JCV-specific CTL developed clinically quiescent PML, while only two out of 11 without detectable CTL controlled their neurological disease. Therefore, the early detection of JCV-specific CTL had an 87% predictive value for subsequent control of PML, while the absence of such CTL had an 82% predictive value for subsequent active PML (P = 0.0009). Fifteen patients were evaluated less than 4 months after the onset of PML (1.9 ± 1.3 months). Of nine patients with JCV-specific CTL, seven (78%) demonstrated subsequent control of disease, whereas six out of six (100%) without JCV-specific CTL developed progressive PML (P = 0.007). Two to ten CTL assays were performed on PBMC of 11 patients. Of these patients, one had an increase in JCV-specific CTL preceding a significant clinical improvement. In another patient with otherwise stable immune parameters, a decline in JCV-specific CTL preceded an exacerbation of PML. We conclude that JCV-specific CTL can be detected early in PML and can predict control of this disease. Fluctuations of JCV-specific CTL in the blood are associated with variation in disease manifestations. These results indicate that JCV-specific CTL are associated with the control of PML.

MRI, 1H-MR spectroscopy, immunologic, and virologic studies were performed in search of prognostic factors of disease evolution in patients with progressive multifocal leukoencephalopathy (PML). Acute lesions of PML survivors showed twofold higher standard score of the ratio of myoinositol (a glial marker) to creatine compared with lesions in patients whose disease progressed. Concomitantly, JC virus-specific cytotoxic T lymphocytes were only detected in the blood of PML survivors. These results suggest that inflammation limits disease progression.

Polyomavirus nephropathy has become an important complication in kidney transplantation, with a prevalence of 1% to 8%. Unfortunately, the risk factors for polyomavirus nephropathy and renal allograft loss are not well defined. The definitive diagnosis is made through assessment of a kidney transplant biopsy. Recently, noninvasive urine and serum markers have been used to assist in polyomavirus nephropathy diagnosis and monitoring. Primary treatment is immunosuppression reduction, but must be balanced with the risks of rejection. No antiviral treatments for polyomavirus nephropathy have been approved by the Food and Drug Administration. Although cidofovir has shown in vitro activity against murine polyomaviruses, and has been effective in some patients, it is associated with significant nephrotoxicity. Graft loss due to polyomavirus nephropathy should not be a contraindication to retransplantation; however, experience is limited. This review presents potential risk factors, screening, diagnostic and monitoring methods, therapeutic management, and retransplantation experience for polyomavirus nephropathy.

Progressive multifocal leukoencephalopathy is a deadly demyelinating disease of the central nervous system, which occurs in immunosuppressed individuals. It is caused by a reactivation of the polyomavirus JC, which induces a lytic infection of oligodendrocytes. This review covers recent developments in the clinical and pathological presentations of progressive multifocal leukoencephalopathy, and advances in the understanding of JC virus biology.

To address the hypothesis that medulloblastoma or supratentorial primitive neuroectodermal tumor (sPNET) can arise through infection by polyomaviruses, we examined genomic DNA isolated from 15 primary medulloblastoma and 5 sPNET biopsy specimens and from 2 medulloblastoma cell lines for the presence of DNA sequences from the polyomaviruses simian virus 40 (SV40), JC virus, and BK virus. These polyomaviruses have oncogenic potential in animals, and their DNA sequences have been detected in other surveys of various solid tumors, including childhood brain tumors. The tumor DNA samples were analyzed by Southern blot hybridization of polymerase chain reaction products that employed probes designed to detect specific polyomavirus sequences. Neither JC virus nor BK virus DNA sequences were detected in any of the specimens. None of the primary medulloblastoma or sPNET specimens contained SV40 sequences. However, SV40 DNA coding and noncoding sequences were detected in the D283-Med (medulloblastoma) cell line. Immunocytochemical studies of D283-Med revealed nuclear expression of SV40 large T antigen. In contrast to childhood ependymomas and choroid plexus tumors, medulloblastomas and sPNETs infrequently express evidence of polyomavirus infection.

ABSTRACTJC virus (JCV), the causative agent of progressive multifocal leukoencephalopathy (PML), has a hypervariable regulatory region (JCV RR). A conserved archetype form is found in the urines of healthy and immunocompromised individuals, whereas forms with tandem repeats and deletions are found in the brains of PML patients. Type I JCV RR, seen in MAD-1, the first sequenced strain of JCV, contains two 98-bp tandem repeats each containing a TATA box. Type II JCV RR has additional 23-bp and 66-bp inserts or fragments thereof and only one TATA box. We cloned and sequenced JCV RR from different anatomic compartments of PML patients and controls and correlated our findings with the patients' clinical outcome. Twenty-three different sequences were defined in 198 clones obtained from 16 patients. All 104 clones with tandem repeats were type II JCV RR. Patients with poor clinical outcome had high proportions of JCV RR clones with both tandem repeats in plasma (54%) and brain or cerebrospinal fluid (85%). In those who became survivors of PML, archetype sequences predominated in these anatomic compartments (75 and 100%, respectively). In patients with advanced human immunodeficiency virus infection without PML, only 8% of JCV RR clones obtained in the plasma contained tandem repeats. These data suggest that the presence of tandem repeats in plasma and CNS JCV RR clones is associated with poor clinical outcome in patients with PML.

ABSTRACTProgressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system caused by a reactivation of the polyomavirus JC (JCV) within a setting of immunosuppression. The nature of the immune response that contains replication of this virus is unknown. We have explored JCV-specific cellular immune responses in patients with PML and control subjects. JCV antigen-stimulated peripheral blood mononuclear cells (PBMC) of four human immunodeficiency virus (HIV)-infected patients who were survivors of PML and one HIV-uninfected patient recently diagnosed with PML lysed autologous B-lymphoblastoid cell lines expressing either the JCV T regulatory protein or the VP1 major capsid protein. This lysis was mediated by CD8+T lymphocytes and was major histocompatibility complex class I restricted. These cells were therefore cytotoxic T lymphocytes (CTL). JCV-specific CTL could not be detected in PBMC of three HIV-infected PML patients who had progressive neurologic disease and an eventual fatal outcome. These data suggest that the JCV-specific cellular immune response may play a crucial role in the containment of PML. This finding may also prove useful as a favorable prognostic marker in the clinical management of these patients.

IMPORTANCE Progressive multifocal leukoencephalopathy results from lytic infection of the glia by the JC polyomavirus (JCV); JCV granule cell neuronopathy is caused by infection with a mutated form of JCV, leading to a shift in viral tropism from the glia to cerebellar granule cells. This shift results in a clinical syndrome dominated by progressive cerebellar dysfunction that might elude standard diagnostic workup strategies for ataxia. OBSERVATIONS We present the case report of a patient receiving long-term rituximab therapy who developed progressive cerebellar ataxia and marked isolated cerebellar degeneration. This syndrome resulted from JCV granule cell neuronopathy associated with a novel JCV mutation. CONCLUSIONS AND RELEVANCE New onset or worsening of isolated cerebellar ataxia in patients being treated with rituximab or natalizumab warrants early assessment for JCV infection.

Seizures are not expected in progressive multifocal leukoencephalopathy (PML), a condition considered to be restricted to the white matter. Review of medical records of 89 patients with possible or proven PML showed an 18% prevalence of seizures. Seizures usually responded well to treatment and did not affect survival. The presence of PML lesions immediately adjacent to the hemispheric cortex was the only risk factor associated with seizures in this population.

Tuberculous meningitis (TBM) is a devastating infection of the central nervous system lacking an adequate point-of-care diagnostic test. We conducted a prospective cohort study of 550 Zambian adults with suspected TBM to determine the diagnostic accuracy of cerebrospinal fluid (CSF) Xpert MTB/RIF, CSF lipoarabinomannan (LAM), urine LAM, CSF total protein, and CSF glucose compared with the gold standard of CSF culture.

The human polyomavirus JC (JCV) infects glial cells and is the etiologic agent of the CNS demyelinating disease progressive multifocal leukoencephalopathy. JCV can infect granule cell neurons of the cerebellum, causing JCV granule cell neuronopathy and cortical pyramidal neurons in JCV encephalopathy. Whether JCV also infects neurons in other areas of the CNS is unclear. We determined the prevalence and pattern of JCV infection of the hippocampus in archival samples from 28 patients with known JCV infection of the CNS and 66 control subjects. Among 28 patients, 11 (39.3%) had JCV infection of hippocampus structures demonstrated by immunohistochemistry. Those included gray matter (dentate gyrus and cornu ammonis, subiculum) in 11/11 and afferent or efferent white matter tracts (perforant path, alveus, fimbria) in 10/11. In the hippocampus, JCV infected granule cell and pyramidal neurons, astrocytes, and oligodendrocytes. Although glial cells expressed either JCV regulatory T Antigen or JCV VP1 capsid protein, infected neurons expressed JCV T Antigen only, suggesting an abortive/restrictive infection. None of the 66 control subjects had evidence of hippocampal JCV protein expression by immunohistochemistry or JCV DNA by in situ hybridization. These results greatly expand our understanding of JCV pathogenesis in the CNS.

Progressive multifocal leukoencephalopathy (PML) is an often-fatal demyelinating disease of the CNS that usually develops in immunocompromised individuals because of reactivation of quiescent JC virus (JCV). There are only a few reports of JCV infection in the human spinal cord. Progressive multifocal leukoencephalopathy—like demyelinating lesions have been documented in the brains of simian immunodeficiency virus—infected macaques. To determine whether simian virus 40 (SV40) can infect and cause PML lesions in spinal cords of immunosuppressed macaques, we examined archival spinal cord samples from 15 simian immunodeficiency virus—infected rhesus monkeys with acquired immunodeficiency syndrome and SV40 infection of the brain. Among those, 6 (40%) had SV40-infected cells in the spinal cord, including 1 with PML-like lesions, 1 with PML-like lesions and meningoencephalitis, 2 with meningoencephalitis, 1 with gray matter gliosis, and 1 with no lesions. One animal with a large PML-like lesion had extensive demyelination and SV40 infection of astrocytes, oligodendrocytes, and meningeal cells. None of the 6 animals had SV40-infected spinal cord neurons. These observations indicate that, like JCV in immunosuppressed humans, SV40 can infect glial cells and cause PML-like lesions in the spinal cord of immunosuppressed rhesus macaques. Rhesus macaques could serve as an animal model to study polyomavirus infection and pathogenesis in the spinal cord.

The human polyomavirus JC (JCV) infects glial cells in immunosuppressed individuals, leading to progressive multifocal leukoencephalopathy. Polyomavirus JC can also infect neurons in patients with JCV granule cell neuronopathy and JCV encephalopathy. CD8-positive T cells play a crucial role in viral containment and outcome in progressive multifocal leukoencephalopathy, but whether CD8-positive T cells can also recognize JCV-infected neurons is unclear. We used immunohistochemistry to determine the prevalence of T cells in neuron-rich areas of archival brain samples from 77 patients with JCV CNS infections and 94 control subjects. Neurons predominantly sustained a restrictive infection with expression of JCV regulatory protein T antigen (T Ag), whereas glial cells were productively infected and expressed both T Ag and the capsid protein VP1. T cells were more prevalent near JCV-infected cells with intact nuclei expressing both T Ag and VP1 compared with those expressing either protein alone. CD8-positive T cells also colocalized more with JCV-infected glial cells than with JCV-infected neurons. Major histocompatibility complex class I expression was upregulated in JCV-infected areas but could only be detected in rare neurons interspersed with infected glial cells. These results suggest that isolated neurons harboring restrictive JCV infection do not upregulate major histocompatibility complex class I and thus may escape recognition by CD8-positive T cells.

Natalizumab, a monoclonal antibody directed against α4 integrins, has, to date, been associated with 399 cases of progressive multifocal leukoencephalopathy (PML) worldwide in patients receiving treatment for multiple sclerosis (MS). Because of the limited number of histologic studies, the possible interplay between MS and PML lesions has not been investigated. We report the clinical, radiologic, and histologic findings of an MS patient who developed PML after 32 months of natalizumab monotherapy. After withdrawal of natalizumab, she received plasma exchange, mefloquine, and mirtazapine but died soon thereafter. Postmortem examination was restricted to examination of the brain and spinal cord. Extensive PML lesions, characterized by the presence of JC virus DNA were found in the cerebral white matter and neocortex. Sharply demarcated areas of active PML lesions contained prominent inflammatory infiltrates composed of approximately equal numbers of CD4-positive and CD8-positive T cells, consistent with an immune reconstitution inflammatory syndrome. Conversely, all MS lesions identified were hypocellular, long-standing inactive plaques characterized by myelin loss, relative axonal preservation, and gliosis and, importantly, were devoid of JC virus DNA and active inflammation. Chronic inactive MS lesions were separate and distinct from nearby PML lesions. This case demonstrates the coexistence and apparent lack of interplay between chronic inactive MS and PML lesions, and that immune reconstitution inflammatory syndrome seems to affect the shape and appearance of PML but not MS lesions.

The human polyomavirus JC (JCV) infects glial cells and causes progressive multifocal leukoencephalopathy (PML), a demyelinating disease of the brain, in immunosuppressed individuals. The extent of JCV infection of neurons is unclear. We determined the prevalence and pattern of JCV infection in gray matter (GM) by immunostaining in archival brain samples of 49 PML patients and 109 control subjects. Among PML patients, 96% had demyelinating lesions in white matter and at the gray-white junction (GWJ); 57% had them in the GM. Most JCV-infected cells in GWJ and GM were glia, but JCV also infected neurons in PML lesions at the GWJ of 54% and GM of 50% patients and in GM outside areas of demyelination in 11% of patients. The JCV regulatory T antigen (Ag) was expressed more frequently in cortical neurons than the VP1 capsid protein. None of the control subjects without PML had any cells expressing JCV proteins. Thus, the cerebral cortex often harbors demyelinating lesions of PML, and JCV infection of cortical neurons is frequent in PML patients. The predominance of T Ag over VP1 expression suggests a restrictive infection in neurons. These results indicate that JCV infection of cerebral cortical neurons is a previously underappreciated component of PML pathogenesis.

Progressive multifocal leukoencephalopathy (PML) occurs most often in immunosuppressed individuals. The lesions of PML result from astrocyte and oligodendrocyte infection by the polyomavirus JC (JCV); JCV has also been shown to infect and destroy cerebellar granule cell neurons (GCNs) in 2 human immunodeficiency virus (HIV)-positive patients. To determine the prevalence and pattern of JCV infection in GCNs, we immunostained formalin-fixed paraffin-embedded cerebellar samples from 40 HIV-positive and 3 HIV-negative PML patients for JCV, and glial and neuronal markers. The JCV infection was detected in 30 patients (70%); 28 (93%) of them had JCV-infected cells in the GC layer; JCV-infected GCNs were demonstrated in 15 (79%) of 19 tested cases. The JCV regulatory T antigen was expressed more frequently and abundantly in GCNs than JCV VP1 capsid protein. None of 37 HIV-negative controls but 1 (3%) of 35 HIV-positive subjects without PML had distinct foci of JCV-infected GCNs. Thus, JCV infection of GCNs is frequent in PML patients and may occur in the absence of cerebellar white matter demyelinating lesions. The predominance of Tantigen over VP1 expression in GCNs suggests that they may be the site of early or latent central nervous system JCV infection. These results indicate that infection of GCNs is an important, previously overlooked, aspect of JCV pathogenesis in immunosuppressed individuals.

There currently is no animal model of JC virus-associated progressive multifocal leukoencephalopathy (PML). Reactivation of simian virus 40 (SV40) in immunosuppressed rhesus monkeys, however, rarely causes a PML-like illness. We sought to isolate a neurotropic clone of SV40 and determine its pathogenic potential in monkeys. The clone SV40CNS1 was amplified by polymerase chain reaction from the brain DNA of a simian/human immunodeficiency virus-infected monkey that had developed PML and meningoencephalitis. Compared with the SV40 prototype 776, SV40CNS1 had a small number of single-amino-acid mutations and caused a productive infection in monkey fibroblasts. It was inoculated into 2 SV40-negative, simian/human immunodeficiency virus-immunosuppressed monkeys. Both animals developed meningoencephalitis with productive SV40 infection of cerebral cortical neurons and glia in the superficial layers of the cortex and at the gray-white junction. Focal SV40-infected cells were also found in the cerebellar molecular and granule cell layers and white matter. Both animals also developed disseminated SV40 infection with nephritis and pneumonitis. Thus, SV40CNS1 is infectious and pathogenic in immunosuppressed monkeys, but it induces encephalitis with fulminant productive infection in cortical neurons and systemic disease, rather than PML. These findings shed new light on SV40 neurotropism and expand the host cell range of this virus.

The human polyomavirus JC (JCV) is the etiologic agent of progressive multifocal leukoencephalopathy (PML), a demyelinating disease of the CNS that occurs in immunosuppressed individuals. Because polyomavirus-induced CNS pathology usually occurs as a result of the reactivation of latent virus, little is known about the disease manifestations of a primary polyomavirus-induced disease in man. To model such a primary infection, SV40-negative rhesus monkeys were immunosuppressed by infection with the virus SHIV-89.6P and then superinfected with the polyomavirus SV40. The animals developed CNS pathology characterized by both demyelination and meningoencephalitis. This observation suggests that a primary polyomavirus infection can be associated with an inflammatory CNS process. These data shed new light on the pathogenic mechanisms of primate polyomaviruses in the immunocompromised host.