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Progressive multifocal leukoencephalopathy (PML) is a rare demyelinating disease caused by John Cunningham virus (JCV) that affects immunocompromised individuals, particularly human immunodeficiency virus (HIV)-positive. Classical symptoms of PML alter mental status, causing paralysis and diplopia. Bizarre presentations, such as seizures and personality change, are rare in PML, which may lead to a delay in diagnosis and treatment. A 31-year-old HIV-positive Malay man on antiretroviral therapy (ART), presented with two episodes of generalized tonic-clonic seizures. First brain MRI showed a solitary right frontal lobe lesion, for which brain biopsy revealed inflammatory infective process with normal cerebrospinal fluid (CSF) examination, and led to diagnosis of primary lymphoma. Four months later, the patient developed progressive personality changes, reduced cognitive function, and left upper limb paralysis. Second brain MRI showed progression of asymmetrical distribution of white matter changes involving sub-cortical, deep, and periventricular area, a classical feature of PML. ART and intensive neuro-rehabilitation were continued, and the patient's condition slowly improved; however, cognitive function remained affected. Our case is the first reported case of PML with HIV, who survived six years after diagnosis despite initial diagnostic dilemma and poor prognostic factors. This case illustrates that survival is possible with compliance with ART and intensive rehabilitation. [ABSTRACT FROM AUTHOR]

The article describes the case of a 63-year-old man, previously treated for COVID-19, who developed foul-smelling blackish discharge from the nasal cavities. Cited are the medical history of the patient, the findings of physical and laboratory investigations which led to the diagnosis of progressive multifocal leukoencephalopathy, and patient outcome following treatment with amphotericin B and posaconazole.

Introduction: Both chronic lymphocytic leukemia (CLL) itself and the drugs used for its treatment, pose a risk for progressive multifocal leukoencephalopathy (PML). Although the relationship between Rituximab and PML is well known, case reports that have been recently published, suggest that ibrutinib; which is used in the treatment of CLL, may increase the risk of PML. Case report: Here, we report a case of 64 year-old female patient with CLL who was previously treated with rituximab, fludarabine and bendamustin but developed PML after receiving monotherapy with ibrutinib. According to Naranjo's algorithm, the causality relationship with the drug is possible with a score of 3. The patient initially exhibited neurological symptoms. Magnetic resonance of the brain revealed a bilateral asymmetric hyperintensity in the white matter involving the parietal and occipital lobules, and there was no mass effect, edema, hemorrhagic or iscemic lesions. No enhancement of contrast media was observed. The findings were consistent with demyelination and suggestive of PML. Management and outcome: Mirtazapine treatment was initiated. However, neurological sympthoms continuously progressed over the following weeks and the patient, aged 64, died six weeks after diagnosis of PML. Discussion: PML is a rare and often fatal demyelinating disease of the central nervous system (CNS) that is exclusively seen in immunocompromised patients and there is no specific agent to treat PML. The case discussed here, highlights that the use of ibrutinib in chronic lymphocytic leukemia (CLL) therapy may result in PML. [ABSTRACT FROM AUTHOR]

The article presents the case of a 34-year-old female with congenital human immunodeficiency virus (HIV)/AIDS who was rushed to a clinic due to 10 days of intermittent right arm and leg shaking movements to discuss new onset focal tremor in patient with HIV. She is undergoing antiretroviral therapy (ART). She was eventually diagnosed with progressive multifocal leukoencephalopathy.

Progressive Multifocal Leukoencephalopathy (PML) represents an opportunistic infection of the central nervous system caused by the JC virus. This entity can appear in various pathologies in immunosuppressed hosts, mainly in patients with HIV / AIDS, however, up to 3% of cases can occur in immunocompetent people. In cases where the disease occurs in immunosuppressed patients, it may be due to two circumstances; the first, to the absence of treatment for the primary pathology, in this case HIV, and the second, as part of an immune reconstitution syndrome (IRS) after the initiation of antiretroviral the rapy. The fundamental importance between these two circumstances is the treatment. While antiretroviral-free patients benefit from the initiation of these drugs, SRI patients benefit from the use of corticosteroids. The definitive PML diagnosis is histopathological, where the triad of demyelination, atypical astrocytes, and nuclear inclusion bodies in oligodendrocytes is classically presented. [ABSTRACT FROM AUTHOR]

Use of cocaine can cause neorologic disorders such as hemorrhagic and ischemic cerebrovascular disease, seizure, neuropsychiatric complications, movement disorders, cerebral vasculitis, reversible cerebral vasoconstriction syndrome, and multifocal leukoencephalopathy. Among them, multifocal inflammatory leukoencephalopathy occurs rarely and is found to be related with a cocaine adulterant, levamisole. In this report, a case of cocaine/levamisole-related multifocal inflammatory leukoencephalopathy appearing with clinical features of catatonia is presented. A 34-year-old female patient was evaluated with symptoms of loss of contact and abnormal behaviour at the emergency department. She was living in Austria and had used cocaine three weeks before admission to hospital. A neurologic examination revealed increased speech latency, echolalia, and poor cooperation. Cranial magnetic resonance imaging showed bilateral fluid-attenuated inversion recovery and T2 hyperintense round-oval shaped lesions with patchy restricted diffusion and heterogenous contrast enhancement in subcortical periventricular white matter. Cranial imaging findings mimicked demyelinating diseases in this patient. Probable use of levamisole-adulterated cocaine, by enhancing immune response, caused levamisole-related multifocal leukoencephalopathy. The patient was started on pulse methylprednisolone treatment. At the request of the patient, on the sixth day of the treatment, she was transferred abroad and further follow-up could not be made. It is known that the use of levamisole, either for medical purpose or as an illegal substance, triggers multifocal leukoencephalopathy by means of complex immune mechanisms. The clinical presentation, radiologic impression, and histological findings of this condition are compatible with demyelinating diseases. Given the increased incidence use of cocaine with its most common adulterant levamisole, recognition and clinical management of its neurologic complications is crucial. [ABSTRACT FROM AUTHOR]

Progressive multifocal leucoencephalopathy (PML) is a demyelinating white matter disease that most often affects immunocompromised people infected by JC virus. The diagnostic gold standard is demonstrable viral DNA or protein from histopathological tissue. However, there are few detailed descriptions of cortical grey matter involvement on neuroimaging. Here we describe the histopathological correlate of cerebral grey matter involvement and radiological accompaniment in a patient with biopsy proven PML. [ABSTRACT FROM AUTHOR]

Background: Progressive multifocal leukoencephalopathy (PML) is a demyelinating disorder caused by JC virus (JCV). Although detecting JCV DNA in the cerebrospinal fluid (CSF) by real-time polymerase chain reaction (PCR) is useful, diagnosis is difficult when JCV concentrations are low. We therefore aimed to lower the detection limit of real-time PCR testing by enriching JCV in the CSF via ultrafiltration.Methods: Virus suspensions and CSF specimens from 20 untreated patients with suspected PML were collected and total DNAs were extracted. The JCV large T gene was detected by quantitative real-time PCR under condition with and without prior centrifugal ultrafiltration.Results: The JCV DNA was reliably detected to a lower limit of 10 copies/mL of virus suspension by real-time PCR with ultrafiltration. When using this method, the quantity of JCV DNA per PCR reaction increased 3.2- to 8.7-fold compared with the standard procedure. Seven patients were positive for JCV when using the standard procedure, and an additional patient was positive when using ultrafiltration. All JCV-positive patients had neurological features and magnetic resonance imaging findings compatible with PML.Conclusions: The detection limit of JCV DNA by real-time PCR can be lowered by viral enrichment using ultrafiltration. Our simple protocol offers a valuable tool for PML diagnosis when extremely low copy numbers of JCV are released into the CSF or when brain biopsy is not feasible. [ABSTRACT FROM AUTHOR]

Progressive multifocal leukoencephalopathy rarely occurs in patients with multiple myeloma. Intracranial central nervous system invasion is also an uncommon event in multiple myeloma, occurring in less than 1% of cases. We describe herein an exceptional case of coexisting progressive multifocal leukoencephalopathy and intraparenchymal central nervous system myeloma infiltration. A 73-year-old woman with relapsed multiple myeloma was treated with 15 cycles of lenalidomide and dexamethasone, but therapy had to be stopped because of a hip fracture after a fall. During hospitalization, the patient developed progressive multifocal leukoencephalopathy caused by John Cunningham virus, and a prominent intra-parenchymal CD138-positive infiltrate was detected. VDJ rearrangements of the immunoglobulin heavy chain gene and the mutational profile of plasma cells in bone marrow at the time of diagnosis and in brain biopsy after progression were analyzed by next generation sequencing, showing genetic differences between medullary and extramedullary myeloma cells. The role of long-term treatment with lenalidomide and dexamethasone in the development progressive multifocal leukoencephalopathy or intraparenchymal central nervous system myeloma infiltration remains unknown. However, our results suggest that both events may have arisen as a consequence of treatment-related immunosuppression. Thus, an appropriate clinical approach compatible with the simultaneous treatment of progressive multifocal leukoencephalopathy and multiple myeloma should be developed. [ABSTRACT FROM AUTHOR]

Adult‐onset leucoencephalopathy with axonal spheroids and pigmented glia (ALSP), also known as hereditary diffuse leucoencephalopathy with spheroids (HDLS), is a progressive neurocognitive disorder that predominantly affects the cerebral white matter, mainly the frontal subcortical areas and the corpus callosum. Patients with ALSP are clinically characterized by a gradual onset of cognitive and behavioural dysfunction and personality changes, followed by motor impairments such as gait disturbance and bradykinesia. Given the disease‐related degenerative changes of the frontal white matter, it is no wonder that patients with ALSP present with behavioural symptoms and non‐fluent aphasia, which are found in patients with frontotemporal lobar degeneration. However, behavioural symptoms and non‐fluent aphasia in a patient with ALSP have rarely reported in detail. Here, we describe a patient with ALSP who initially presented with remarkable behavioural signs and non‐fluent primary progressive aphasia, which resembled symptoms of frontotemporal lobar degeneration. The present case suggests that ALSP should be included in the differential diagnosis for frontotemporal lobar degeneration. [ABSTRACT FROM AUTHOR]

Oxycodone-induced leukoencephalopathy is a rare diagnosis that should be considered in unconscious patients with appropriate history. We describe a case of a 57-year-old unconscious woman who required intubation and did not respond to naloxone infusion. The unconsciousness was initially thought to be due to hypoxic brain injury. However, a further review of brain imaging showed characteristic features of oxycodone-induced leukoencephalopathy. We describe the pathological and radiological features of this condition, and provide a concise review of the limited literature on this condition. Accurate diagnosis of this condition will be valuable to clinicians and patients in terms of their medium-term and long-term prognosis, and potential for rehabilitation. [ABSTRACT FROM AUTHOR]

Objectives: Up to 20% of HIV‐related focal brain lesion (FBL) diagnoses cannot be determined without invasive procedures. In such cases, brain biopsy is an important step in the evaluation algorithm. The aims of this study were to describe the clinical outcomes of patients with FBL, the proportion of diagnoses confirmed by brain biopsies and their aetiologies, and to analyse the proportion of patients in whom the biopsy motivated a change in therapeutic management. Methods: A retrospective cohort study was performed. The data from clinical records of patients with HIV‐related FBL admitted between January 2005 and December 2015 were reviewed. Results: A total of 137 patients were included in the study. The median age was 39 years [interquartile range (IQR) 33–44.5 years]. The median CD4 count was 54 cells/μL (IQR 21–124 cells/μL). Cerebral brain biopsy was performed in 21.16% of patients (29 of 137); 68.9% of these individuals (20 of 29) were diagnosed by histology, with results of central nervous system (CNS) lymphoma in 20.6% (six of 29), progressive multifocal leucoencephalopathy in 6.8% (two of 29), toxoplasmosis in 6.8% (two of 29), tuberculoma in 6.8% (two of 29), and other diagnoses in 27.6% (eight of 29). In nine patients, the histology was nonspecific. In 75.8% of patients (22 of 29), the result of the biopsy led to a change in the therapeutic management. We did not observe higher rates of mortality related to the procedure. Overall mortality at 30 and 90 days was similar in patients who were and were not biopsied. Conclusions: In this retrospective cohort study, cerebral biopsy was associated with significant adjustments in therapeutic management for a high percentage of patients. [ABSTRACT FROM AUTHOR]

Background. Progressive multifocal leukoencephalopathy (PML) is a severe demyelinating disease caused by the polyomavirus JC (John Cunningham; JCV) that affects patients with impaired immune systems. While JCV-DNA detection in cerebrospinal fluid (CSF) is diagnostic of PML, the clinical significance of plasma JCV-DNA is uncertain. Methods. We retrospectively analyzed plasma samples from PML patients that were drawn close to disease onset and from controls without PML. In PML patients, we compared plasma JCV-DNA detection and levels to clinical and laboratory parameters, and patient survival. Results. JCV-DNA was detected in plasma of 49/103 (48%) patients with PML (20/24, 83%, human immunodeficiency virus [HIV] negative; 29/79, 37%, HIV-positive) and of 4/144 (3%) controls without PML (0/95 HIV-negative; 4/49, 8%, HIV-positive), yielding a diagnostic sensitivity and specificity of 48% and 97% (83% and 100% in HIV-negative; 37% and 92% in HIV-positive), respectively. Among 16 PML patients with undetectable CSF JCV-DNA, 4 (25%) had detectable plasma JCV-DNA. Plasma JCV-DNA levels were independently associated with CSF levels (P < .0001) and previous corticosteroid treatment (P = .012). Higher plasma JCV-DNA levels were associated with disease progression in HIV-negative patients (P = .005); in HIV-positive patients, there was an increased risk of progression only in those treated with combination antiretroviral therapy (cART; P < .0001). Conclusions. Testing JCV-DNA in plasma might complement PML diagnosis, especially when CSF is unavailable or JCV-DNA not detectable in CSF. In addition, JCV-DNA plasma levels could be useful as a marker of disease progression in both HIV-negative and cART-treated, HIV-positive PML patients. [ABSTRACT FROM AUTHOR]

The article offers information on a study to assess the effectiveness of fumaric acid esters for treatment of psoriasis and mentions occurence of progressive multifocal leukoencephalopathy in areas treated with dimethyl fumarate preparations. It discusses the evaluation of immunosuppression and lymphopenia in patients treated with azathioprine. It also states predictions of lymphopenia during switching of dimethyl fumarate from natalizumab therapy and baseline lymphocyte counts.

A case study of a 46‑year‑old female patient presented with progressive bilateral painless visual diminution along with cognitive impairment for 3 months. Topics include the increasing use of immunomodulatory therapy for rheumatological diseases and multiple sclerosis, its incidence in non‑HIV populations; and Progressive multifocal leukoencephalopathy (PML) occurs due to the re‑activation of the polyoma John Cunningham (JC) virus in immunocompromised patients.

A case study of a 42‑year‑old gentleman with prior comorbidities presented with the sub‑acute onset and progressive weakness with slurring of speech with impaired comprehension. Topics include Whole‑body positron emission tomography scan revealed areas of hypometabolism in the left fronto‑parietal and right parieto‑occipital region; and multiple well‑defined hyperintense lesions in the subcortical and deep white matter of both cerebral hemispheres with peripheral foci of satellite lesions.

Introduction: Brain as the seat of behavior is acknowledged from the times of Charaka, however where neurology ends and philosophy begins remains an enigma. It is certainly every neurologist's observation that there is loss of function either region based or domain based in progressive diseases of the nervous system making it the seat of all useful activities. However, there are references to occurrence of new skills seen during various illnesses causing progressive cognitive dysfunction. This serves as a pharmaco-sparing agent in behavior management and therefore serves as a rehabilitatory tool. However, its pathomechanism is not clear. Patient and Methods: Two patients comprising one male and one female who were being evaluated for progressive cognitive dysfunction and were found to have interesting creative skills and are being described. Results: The first patient is a case of young onset behavioral variant frontotemporal dementia and the second patient is a case of neurosarcoidosis. Conclusion: The emergence of these skills could be due to disinhibition of some of the innate skills of the patients during degeneration or establishment of new data linking circuits with creative potential during attempted repair. [ABSTRACT FROM AUTHOR]

Purpose: The JLGK0901 study showed the noninferiority of stereotactic radiosurgery (SRS) alone as initial treatment of 5 to 10 brain metastases (BMs) compared with 2 to 4 BMs in terms of overall survival and most secondary endpoints (Lancet Oncol 2014;15:387-95). However, observation periods were not long enough to allow confirmation of the long-term safety of SRS alone in patients with 5 to 10 BMs.Methods and Materials: This was a prospective observational study of Gamma Knife SRS-treated patients with 1 to 10 newly diagnosed BMs enrolled at 23 facilities between March 1, 2009, and February 15, 2012.Results: The 1194 eligible patients were categorized into the following groups: group A, 1 tumor (n=455); group B, 2 to 4 tumors (n=531); and group C, 5 to 10 tumors (n=208). Cumulative rates of Mini-Mental State Examination (MMSE) score maintenance (MMSE score decrease <3 from baseline) determined with a competing risk analysis of groups A, B, and C were 93%, 91%, and 92%, respectively, at the 12th month after SRS; 91%, 89%, and 91%, respectively, at the 24th month; 89%, 88%, and 89%, respectively, at the 36th month; and 87%, 86%, and 89%, respectively, at the 48th month (hazard ratio [HR] of group A vs group B, 0.719; 95% confidence interval [CI], 0.437-1.172; P=.18; HR of group B vs group C, 1.280; 95% CI, 0.696-2.508; P=.43). During observations ranging from 0.3 to 67.5 months (median, 12.0 months; interquartile range, 5.8-26.5 months), as of December 2014, 145 patients (12.1%) had SRS-induced complications. Cumulative complication incidences by competing risk analysis for groups A, B, and C were 7%, 8%, and 6%, respectively, at the 12th month after SRS; 10%, 11%, and 11%, respectively, at the 24th month; 11%, 11%, and 12%, respectively, at the 36th month; and 12%, 12%, and 13%, respectively, at the 48th month (HR of group A vs group B, 0.850; 95% CI, 0.592-1.220; P=.38; HR of group B vs group C, 1.052; 95% CI, 0.666-1.662, P=.83). Leukoencephalopathy occurred in 12 of the 1074 patients (1.1%) with follow-up magnetic resonance imaging and was detected after salvage whole-brain radiation therapy in 11 of these 12 patients. In these 11 patients, leukoencephalopathy was detected by magnetic resonance imaging 5.2 to 21.2 months (median, 11.0 months; interquartile range, 7.0-14.4 months) after whole-brain radiation therapy.Conclusions: Neither MMSE score maintenance nor post-SRS complication incidence differed among groups A, B, and C. This longer-term follow-up study further supports the already-reported noninferiority hypothesis of SRS alone for patients with 5 to 10 BMs versus 2 to 4 BMs. [ABSTRACT FROM AUTHOR]

We, herein, report a 23-year-old male with a rare inherited immunodeficiency disease, hyperimmunoglobulin IgE syndrome (HIES), who developed progressive multifocal leukoencephalopathy (PML) and lymphoma simultaneously. Primary immunodeficiency of the patient has remained undiagnosed until adulthood. PML is a severe demyelinating disease of the central nervous system caused by John Cunningham virus. HIES is a rare, inherited immunodeficiency characterized by high serum levels of IgE, recurrent staphylococcal infection, eczema, and hypereosinophilia. PML may accompany primary immunodeficiency syndromes, but the association with HIES is exceedingly rare. We discuss the imaging findings, medical management, and a review of related literature on primary immunodeficiency cases complicating with PML. [ABSTRACT FROM AUTHOR]

Progressive multifocal leucoencephalopathy (PML) is a progressive demyelinating condition resulting from infection with the John Cunningham virus and precipitated by immunocompromised states. The HIV pandemic, especially in sub-Saharan Africa, has resulted in an increase in the number of patients presenting with PML. Imaging plays an important role in diagnosis and the distribution of the disease is predominantly supratentorial. Isolated posterior fossa involvement is a rare finding with very few cases described in the literature. We present the largest case series of patients described in the literature, with isolated posterior fossa involvement of PML, in HIV-positive patients. [ABSTRACT FROM AUTHOR]

Objective: Progressive multifocal leukoencephalopathy (PML) is an emerging complication of immunosuppressive therapies, especially natalizumab in multiple sclerosis (MS). Factors associated with functional outcome of natalizumab-associated PML (natalizumab-PML) have not been sufficiently described. Methods: We retrospectively analyzed medical records of all patients with natalizumab-PML (n = 32) treated in our hospital since 2009. Disability measured by Expanded Disability Status Scale (EDSS) at two different time points (highest available EDSS during PML and last available EDSS after PML diagnosis) served as functional outcome parameters. Clinical, laboratory, and imaging data were analyzed for association with functional outcome by applying Spearman’s rho and multivariate regression analysis. Results: In all, 31/32 patients survived PML. A poor functional outcome was associated with higher age, higher initial John Cunningham virus (JCV) copy number in cerebrospinal fluid (CSF), and more extensive PML lesions on initial magnetic resonance imaging (MRI). No association between functional outcome and the duration of natalizumab therapy or a delayed PML diagnosis was observed. Conclusion: This study will be useful for neurological practice to estimate functional outcome or disease severity of natalizumab-PML in primary care settings. [ABSTRACT FROM AUTHOR]

Progressive multifocal leukoencephalopathy (PML) is a devastating neurological disease observed nearly exclusively in immunocompromised patients. Recently, the introduction of monoclonal antibodies significantly inhibiting the immune system such as rituximab has led to an increase in PML cases. Although rituximab-based immunochemotherapy remains the standard of treatment for chronic lymphocytic leukemia (CLL), the importance of Bruton's tyrosine kinase inhibitors such as ibrutinib is steadily increasing. However, long-term experiences regarding possible side effects of these new substances are rare. Here, we report the development of eventually fatal PML possibly associated with ibrutinib therapy for CLL after multiple prior treatment lines, including rituximab. To the best of our knowledge, this is the first study to report such findings. Since the last course of rituximab was applied over 3 years ago, it is conceivable that the strong B cell inhibition by ibrutinib led to PML. With increased awareness of this potential side effect, further clinical studies are certainly warranted to evaluate this possible association. [ABSTRACT FROM AUTHOR]

The article presents a case study of a 78-year-old woman presented with slurred speech and right-hand clumsiness. Topics include progressive multifocal leukoencephalopathy (PML) has a demyelinating disease of the CNS caused by reactivation of the oligodendrocyte; and PML has an adverse reaction to systemic immunomodulating drugs such as steroids, cyclophosphamide, and rituximab.

The article describes the case of a 40-year-old white male who was admitted with new diagnoses of human immunodeficiency virus (HIV) and progressive multifocal leukoencephalopathy. The patient was administered antiretroviral therapy on the sixth day which was initiated enterally with abacavir, lamivudine, and raltegravir. The therapy resulted in mild mental status improvement and orientation to self and his family members.

The article presents a case study 68-year-old man with familial idiopathic pulmonary fibrosis history following a bilateral ling transplant. The man suffered from progressive behavioral changes, gain instability, short-term memory loss, and word-finding difficulties. Hypointensity in the frontal lobe white matter was noted through brain magnetic resonance imaging. A diagnosis of progressive multifocal leukoencephalopathy was made.

Background. Natalizumab- (NTZ-) associated progressive multifocal leukoencephalopathy (PML) is a severe and often disabling infectious central nervous system disease that can become evident in multiple sclerosis (MS) patients after NTZ discontinuation. Recently, novel diagnostic biomarkers for the assessment of PML risk in NTZ treated MS patients such as the anti-JC virus antibody index have been reported, and the clinical relevance of milky-way lesions detectable by MRI has been discussed. Case Presentation and Conclusion. We report a MS patient in whom PML was highly suspected solely based on MRI findings after switching from NTZ to fingolimod despite repeatedly negative (ultrasensitive) polymerase chain reaction (PCR) testing for JC virus DNA in cerebrospinal fluid. The PML diagnosis was histopathologically confirmed by brain biopsy. The occurrence of an immune reconstitution inflammatory syndrome (IRIS) during fingolimod therapy, elevated measures of JCV antibody indices, and the relevance of milky-way-like lesions detectable by (7 T) MRI are discussed. [ABSTRACT FROM AUTHOR]

Nearly 30 years after the advent of antiretroviral therapy (ART), CNS opportunistic infections remain a major cause of morbidity and mortality in HIV-positive individuals. Unknown HIV-positive disease status, antiretroviral drug resistance, poor drug compliance, and recreational drug abuse are factors that continue to influence the morbidity and mortality of infections. The clinical and radiographic pattern of CNS opportunistic infections is unique in the setting of HIV infection: opportunistic infections in HIV-positive patients often have characteristic clinical and radiological presentations that can differ from the presentation of opportunistic infections in immunocompetent patients and are often sufficient to establish the diagnosis. ART in the setting of these opportunistic infections can lead to a paradoxical worsening caused by an immune reconstitution inflammatory syndrome (IRIS). In this Review, we discuss several of the most common CNS opportunistic infections: cerebral toxoplasmosis, progressive multifocal leukoencephalopathy (PML), tuberculous meningitis, cryptococcal meningitis and cytomegalovirus infection, with an emphasis on clinical pearls, pathological findings, MRI findings and treatment. Moreover, we discuss the risk factors, pathophysiology and management of IRIS. We also summarize the challenges that remain in management of CNS opportunistic infections, which includes the lack of phase II and III clinical trials, absence of antimicrobials for infections such as PML, and controversy regarding the use of corticosteroids for treatment of IRIS. [ABSTRACT FROM AUTHOR]

The implementation of a variety of immunosuppressive therapies has made drug-associated progressive multifocal leukoencephalopathy (PML) an increasingly prevalent clinical entity. The purpose of this study was to investigate its diagnostic characteristics and to determine whether differences herein exist between the multiple sclerosis (MS), neoplasm, post-transplantation, and autoimmune disease subgroups. Reports of possible, probable, and definite PML according to the current diagnostic criteria were obtained by a systematic search of PubMed and the Dutch pharmacovigilance database. Demographic, epidemiologic, clinical, radiological, cerebrospinal fluid (CSF), and histopathological features were extracted from each report and differences were compared between the disease categories. In the 326 identified reports, PML onset occurred on average 29.5 months after drug introduction, varying from 14.2 to 37.8 months in the neoplasm and MS subgroups, respectively. The most common overall symptoms were motor weakness (48.6 %), cognitive deficits (43.2 %), dysarthria (26.3 %), and ataxia (24.1 %). The former two also constituted the most prevalent manifestations in each subgroup. Lesions were more often localized supratentorially (87.7 %) than infratentorially (27.4 %), especially in the frontal (64.1 %) and parietal lobes (46.6 %), and revealed enhancement in 27.6 % of cases, particularly in the MS (42.9 %) subgroup. Positive JC virus results in the first CSF sample were obtained in 63.5 %, while conversion after one or more negative outcomes occurred in 13.7 % of cases. 52.2 % of patients died, ranging from 12.0 to 83.3 % in the MS and neoplasm subgroups, respectively. In conclusion, despite the heterogeneous nature of the underlying diseases, motor weakness and cognitive changes were the two most common manifestations of drug-associated PML in all subgroups. The frontal and parietal lobes invariably constituted the predilection sites of drug-related PML lesions. [ABSTRACT FROM AUTHOR]

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 1 year 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 1 year 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 5.4 months (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. [ABSTRACT FROM AUTHOR]

Background: Natalizumab provides rapid and high-efficacy control of multiple sclerosis disease activity with long-term stabilization. However, the benefits of the drug are countered by a risk of developing progressive multifocal leukoencephalopathy in patients infected with the John Cunningham Virus. Close monitoring is required in patients with increased progressive multifocal leukoencephalopathy risk receiving natalizumab in the long-term for an optimal benefit-risk evaluation. Standardized high-quality monitoring procedures may provide a superior basis for individual benefit and risk evaluation and thus improve treatment decisions. The non-interventional study TRUST was designed to capture natalizumab effectiveness under real-life conditions and to examine alternate approaches for clinical assessments, magnetic resonance imaging monitoring and use of biomarkers for progressive multifocal leukoencephalopathy risk stratification.Methods/design: TRUST is a non-interventional, multicenter, prospective cohort study conducted at approximately 200 German neurological centers. The study is intended to enroll 1260 relapsing-remitting multiple sclerosis patients with ongoing natalizumab therapy for at least 12 months. Patients will be followed for a period of 3 years, irrespective of treatment changes after study start. Data on clinical, subclinical and patient-centric outcomes will be documented in order to compare the effectiveness of continuous versus discontinued natalizumab treatment. Furthermore, the type and frequency of clinical, magnetic resonance imaging and biomarker assessments, reasons for continuation or discontinuation of therapy and the safety profile of natalizumab will be collected to explore the impact of a systematic patient management approach and its potential impact on patient outcome. Specifically, the role of biomarkers, the use of expert opinions, the impact of high-frequency magnetic resonance imaging assessment for early progressive multifocal leukoencephalopathy detection and the role of additional radiological and clinical expert advice will be explored.Discussion: TRUST was initiated in spring 2014 and enrollment is anticipated to be completed by mid 2016. Annual interim analyses will deliver continuous information and transparency with regard to the patient cohorts and the completeness and quality of data as well as closely monitor any safety signals in the natalizumab-treated cohort. The study's results may provide insights into opportunities to improve the benefit-risk assessment in clinical practice and support treatment decisions. [ABSTRACT FROM AUTHOR]

We investigated delay in diagnosing progressive multifocal leukoencephalopathy ( PML). The median time from initial symptom to diagnosis was 74 days (range 1-1643) in 111 PML patients seen at our institution from 1993 to 2015. Another diagnosis was considered before PML in nearly two-thirds, and more than three-quarters of patients suffered from diagnostic delay greater than 1 month, irrespective of their underlying immunosuppressive condition. Extended diagnostic delay occurred more frequently in patients with possible PML, and among HIV+ patients with higher CD4+ T-cell counts at symptom onset. Prompt diagnosis may improve survival of PML in so far as immune reconstitution can be effected, and prevent unnecessary interventions. [ABSTRACT FROM AUTHOR]

Background Low-signal-intensity (LSI) rim along deep layers of the cerebral cortex is reportedly a susceptibility-weighted imaging (SWI) finding in progressive multifocal leukoencephalopathy (PML). We aimed to evaluate whether this finding can be identified in diseases other than PML. Methods We retrospectively reviewed brain MR images from 5605 patients who underwent SWI at 3T; 370 patients with various diseases, who showed cortical and subcortical FLAIR high-signal lesions including U-fiber, were enrolled. The presence or absence of LSI rim on thin-slice SWI and hyperintense cortical signal (HCS) on T1-weighted images adjacent to LSI rim was analyzed. Signal changes of the LSI rim were assessed on serial SWI, if available. Results Twenty-five of the 370 patients (6.8%) showed SWI LSI rim, in infarct ( n = 22) and encephalitis ( n = 3). HCS was apparent adjacent to SWI LSI rim in 17 patients (15 infarct, 2 encephalitis). Serial SWI was available for 17 patients, of whom 10 patients (8 infarct, 2 encephalitis) presented LSI rim later than 45 days after onset. Conclusion LSI rim can be observed in infarct and encephalitis. Therefore, this finding is not specific to PML. LSI rim appears to be associated with HCS. [ABSTRACT FROM AUTHOR]

Progressive multifocal leukoencephalopathy ( PML), a demyelinating disease of the brain, is typically diagnosed in immunocompromised persons. Here, we describe the diagnostic challenge of PML in an apparently immunocompetent patient. Thorough analyses, including cytokine release assays and whole exome sequencing, revealed a deficit in the antiviral interferon gamma production capacity of this patient and compound heterozygous mutations in BCL-2-associated athanogene 3. Interestingly, both factors are associated with reduced expression of John Cunningham virus T-antigen, a protein that plays a key role in viral replication in infected cells. After validation in other patients, our findings may contribute to novel insights into the etiology and possibly treatment of PML. [ABSTRACT FROM AUTHOR]

This study focused on the molecular characterization of patients with leukoencephalopathy associated with a specific biochemical defect of mitochondrial respiratory chain complex III, and explores the impact of a distinct magnetic resonance imaging pattern of leukoencephalopathy to detect biallelic mutations in LYRM7 in patients with biochemically unclassified leukoencephalopathy. 'Targeted resequencing' of a custom panel including genes coding for mitochondrial proteins was performed in patients with complex III deficiency without a molecular genetic diagnosis. Based on brain magnetic resonance imaging findings in these patients, we selected additional patients from a database of unclassified leukoencephalopathies who were scanned for mutations in LYRM7 by Sanger sequencing. Targeted sequencing revealed homozygous mutations in LYRM7, encoding mitochondrial LYR motif-containing protein 7, in four patients from three unrelated families who had a leukoencephalopathy and complex III deficiency. Two subjects harboured previously unreported variants predicted to be damaging, while two siblings carried an already reported pathogenic homozygous missense change. Sanger sequencing performed in the second cohort of patients revealed LYRM7 mutations in three additional patients, who were selected on the basis of the magnetic resonance imaging pattern. All patients had a consistent magnetic resonance imaging pattern of progressive signal abnormalities with multifocal small cavitations in the periventricular and deep cerebral white matter. Early motor development was delayed in half of the patients. All patients but one presented with subacute neurological deterioration in infancy or childhood, preceded by a febrile infection, and most patients had repeated episodes of subacute encephalopathy with motor regression, irritability and stupor or coma resulting in major handicap or death. LYRM7 protein was strongly reduced in available samples from patients; decreased complex III holocomplex was observed in fibroblasts from a patient carrying a splice site variant; functional studies in yeast confirmed the pathogenicity of two novel mutations. Mutations in LYRM7 were previously found in a single patient with a severe form of infantile onset encephalopathy. We provide new molecular, clinical, and neuroimaging data allowing us to characterize more accurately the molecular spectrum of LYRM7 mutations highlighting that a distinct and recognizable magnetic resonance imaging pattern is related to mutations in this gene. Inter- and intrafamilial variability exists and we observed one patient who was asymptomatic by the age of 6 years. [ABSTRACT FROM AUTHOR]

Anticancer therapy predisposes patients to infections by the immunosuppression that results from treatment. Although 85% of patients with progressive multifocal leukoencephalopathy (PML) have concurrent HIV/AIDS, PML can also develop in patients after they receive chemotherapy for cancer. The case herein describes a 69-year-old man with history of follicular lymphoma who presented with progressive dysarthria and right-sided paralysis. He received rituximab one year prior to presentation. PET scan suggested no recurrence of lymphoma. Cerebrospinal fluid (CSF) analysis was negative and showed fewer than 500 copies/mL of JC virus. However, brain biopsy showed chromatin margination and viropathic change within oligodendrocytes, confirming PML. He was started on mirtazapine and mefloquine with some clinical improvement. To our knowledge, this is the first case of rituximab-associated PML in a patient with negative JC virus PCR from the CSF. Recognition of PML in the differential of oncology patients with CNS symptoms is an important consideration as we enter the era of targeted therapy and personalized cancer medicine involving biologics. Furthermore, screening of patients for presence of subclinical JC viremia prior to the use of biologics may be an important component of assessing patient candidacy for these agents. [ABSTRACT FROM AUTHOR]

A case study is presented of a 64-year-old female presented to the hospital with a history of chest discomfort for two hours. It informs that the patient's electrocardiogram (EKG) revealed sinus bradycardia with an ST elevation and coronary angiography revealed a cardiac wall motion abnormality. It mentions that the patient was offered ranolazine to treat her chronic anginal symptoms.

Multifocal necrotising leucoencephalopathy is a rare disorder affecting the central nervous system. It is characterised pathologically by microscopic areas of necrosis with pontine predilection but also involvement of extrapontine regions, including the cerebellum, medulla and cerebral hemispheres. It usually occurs on the background of immunosuppression. Here we describe an immunocompetent patient with a recent history of Salmonella infection who presented with subacute neurological deterioration. At postmortem, she had evidence of multifocal necrotising leucoencephalopathy. [ABSTRACT FROM AUTHOR]

The presence of anti-John Cunningham Virus (JCV) antibodies is a risk factor for the development of progressive multifocal leukoencephalopathy (PML) in MS patients treated with natalizumab. It has been suggested that an increase in serum anti-JCV antibody index precedes the development of PML. We here describe extensive longitudinal serum anti-JCV antibody indexes of four MS patients who developed PML. Anti-JCV antibodies were measured using the STRATIFY JCV™DxSelect™ test. All four patients had rather stable high anti-JCV antibody indexes in all samples obtained before developing PML. Possibly caused by reaching the saturation level of the assay, no increase in anti-JCV antibody indexes was seen just before the diagnosis of PML. This study confirms that high serum anti-JCV antibody indexes precede natalizumab-associated PML. [ABSTRACT FROM AUTHOR]

Progressive multifocal leukoencephalopathy ( PML) is a fatal demyelinating disease caused by reactivation of the asymptomatic persistent pathogen human polyomavirus JC ( JC virus). The pathology of affected brain tissues demonstrates oligodendroglia-like cells with viral inclusions in their enlarged nuclei, a diagnostic hallmark of this disease. Today, the pathological features of this disease are expanding, partly due to an unsteady balance between viral virulence and host immunity. Intranuclear viral inclusions were initially thought to be amphophilic materials comprising the entire enlarged nucleus, based on HE staining (full inclusions). Howevewr, recent immunohistochemical analyses detected the presence of intranuclear viral inclusions in dots (dot-shaped inclusions). The dot-shaped inclusions reflect clustered progeny virions at punctuated subnuclear domains called promyelocytic leukemia nuclear bodies, and are indicative of early-stage viral infection or suppressed viral proliferation. Second, the JC virus is usually reactivated in patients with impaired immunity, and therefore the inflammatory reactions are poor. However, the causes of immunosuppression are divergent, as seen with the frequent use of immunosuppressive drugs, including natalizumab. Therefore, the degree of host immunity is variable; some patients show marked anti-viral inflammatory reactions and a good prognosis, indicating that a strong resistance against viral infection remains. Recovery of the immune system may also induce paradoxical clinical worsening, known as immune reconstitution inflammatory syndrome, the mechanism of which has not been clarified. The virus-host interactions have increased in complexity, and the pathology of PML is diverging. In this review, the pathology of PML will be described, with a focus on the intranuclear target of JC virus infection and host inflammatory reactions. [ABSTRACT FROM AUTHOR]

Objective: To investigate the MRI manifestation pattern of asymptomatic natalizumab-associated progressive multifocal leukoencephalopathy (PML) in patients with multiple sclerosis (MS). Methods: 18 patients with MS with natalizumab-associated PML lesions on MRI were included. In 6 patients, the PML lesions were identified on MRI prospectively and in 12 patients PML lesions were identified retrospectively. MRI sequences were analysed for PML lesion distribution, appearance, grey matter/white matter involvement and possible signs of inflammation. Lesion probability maps were created to demonstrate lesion distribution pattern. Results: The frontal lobe was involved in 14 patients (77.8%) and the parietal lobe in 4 patients (22.2%). Most patients presented with focal lesions (13 patients, 72.2%) involving one single lobe (12 patients, 66.7%). The cortical grey matter was affected in 15 patients (83.3%) and 13 patients (72.2%) presented with a combination of cortical grey and white matter involvement. Signs of inflammation were detected in 7 patients (38.8%). Among patients with available diffusion-weighted imaging, 6 patients (40%) did not show high-signal-intensity lesions. A classical imaging pattern including unilateral and unilobar focal lesions in the frontal lobe affecting the cortical grey matter or the cortical grey and adjacent white matter was observed in 8 patients (44.4%). Conclusions: Asymptomatic natalizumab-associated PML manifestations on MRI show a rather localised disease, frequently located in the frontal lobes, affecting the cortical grey matter and adjacent juxtacortical white matter. Awareness of this lesion pattern facilitates an earlier diagnosis of natalizumab-associated PML in an asymptomatic stage associated with a more favourable prognosis. [ABSTRACT FROM AUTHOR]

We describe a case with a false-negative PCR-based analysis for JC virus in cerebrospinal fluid (CSF) in a patient with clinical and radiological findings suggestive of progressive multifocal leukoencephalopathy (PML) who was on chronic immunosuppressive therapy for rheumatoid arthritis. Our patient developed rapidly progressive global decline with clinical and radiographic findings suggestive of PML, but JC virus PCR in CSF was negative. The patient passed away 3 months from the onset of her neurological symptoms. Autopsy confirmed the diagnosis of PML with presence of JC-polyoma virus by immunohistochemical staining. This case highlights the potential of false-negative JC virus PCR in CSF when radiographic and clinical features are suggestive of “possible PML.” We review the plausible causes of potential false-negative CSF results and suggest that when the clinical presentation is suspicious for PML repeat CSF analysis utilizing ultrasensitive PCR assay and subsequent brain biopsy should be considered if CSF remains negative. Additionally, appropriate exclusion of other neurologic conditions is essential. [ABSTRACT FROM AUTHOR]

Purpose: A 30 year-old man with a history of recurrent skin infections as well as elevated serum IgE and eosinophils developed neurological symptoms and had T2-hyperintense lesions observed in cerebral MRI. The immune symptoms were attributed to Hyper IgE syndrome (HIES) and the neurological symptoms with presence of JC virus in cerebrospinal fluid were diagnosed as Progressive Multifocal Leukoencephalopathy (PML). The patient was negative for STAT3 mutations. To determine if other mutations explain HIES and/or PML in this subject, his DNA was analyzed by whole genome sequencing. Methods: Whole genome sequencing was completed to 30X coverage, and whole genome SNP typing was used to complement these data. The methods revealed single nucleotide variants, structural variants, and copy number variants across the genome. Genome-wide data were analyzed for homozygous or compound heterozygous null mutations for all protein coding genes. Mutations were confirmed by PCR and/or Sanger sequencing. Results: Whole genome analysis revealed deletions near the telomere of both copies of chromosome 9p. Several genes, including DOCK8, were impacted by the deletions but it was unclear whether each chromosome had identical or distinct deletions. PCR across the impacted region combined with Sanger sequencing of selected fragments confirmed a homozygous deletion from position 10,211 to 586,751. Conclusion: While several genes are impacted by the deletion, DOCK8 deficiency is the most probable cause of HIES in this patient. DOCK8 deficiency may have also predisposed the patient to develop PML. [ABSTRACT FROM AUTHOR]

In the context of 2 patients with hematological malignancy who developed progressive multifocal leukoencephalopathy (PML), we review the current therapeutic options for this serious complication. Both patients had lymphoma and had been pretreated with the antibody rituximab. Diagnosis of PML was obtained upon the detection of the JC virus. The outcome was fatal in both cases. So far, no standard therapeutic approach for JC virus infection has been established in HIV-negative patients with hematological malignancies and the outcome is usually fatal. Serotonin receptor antagonists might have a beneficial effect by blocking the virus from entering the cells. Although hopes for the efficacy of mefloquine were disappointed by the results of 1 study, several case reports describe improvements in neurological impairment when this drug is administered. Taking the desperate situation of this patient group into consideration, the combination of mirtazapine and mefloquine might be worthy of an attempt. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Magnetic resonance imaging (MRI) is a useful tool for diagnosing and monitoring progressive multifocal leukoencephalopathy (PML). Although characteristic MRI findings of PML are well known, we noted a potential new finding for this disease on susceptibility-weighted imaging (SWI). Two patients with PML were studied and followed using MRI. SWI revealed low signal intensities in U-fibers adjacent to the white matter lesions of PML. These findings progressed along with the disease progression. The cause underlying these findings remains unclear. This new finding suggests that SWI is useful for the diagnosis of PML. It can provide a helpful clue in a clinical setting. [ABSTRACT FROM AUTHOR]

Migraine is a kind of common primary headache, which seriously damages human health and quality of life. Recent studies show there is a high incidence of white matter lesions (WML) in migraineurs, which is independent of other risk factors for cerebrovascular diseases. The patent foramen ovale (PFO) in migraineurs, especially in migraineurs with aura, is more common than in general population. There is a close relationship between them, but it is controversial whether it is a causal link. Patent foramen ovale can cause paradoxical embolism, but its role in the pathogenesis of migraine is still unknown. It is worth exploring whether there is difference in white matter lesions between the migraineurs with and without patent foramen ovale. [ABSTRACT FROM AUTHOR]

The diagnosis of natalizumab-associated progressive multifocal leukoencephalopathy (PML) in multiple sclerosis patients in an asymptomatic stage is crucial since it is associated with better clinical outcome measures. Current diagnostic criteria on PML diagnosis in asymptomatic patients require the detection of JC virus and corresponding imaging findings. Magnetic resonance imaging (MRI) is the most sensitive diagnostic method for these purposes. However, the diagnosis of asymptomatic natalizumab-associated PML based on MRI findings can be challenging particularly in case of inconclusive or negative results on JC virus detection in the cerebrospinal fluid. In this report, we present a case series demonstrating different diagnostic scenarios of asymptomatic PML diagnosis based on MRI findings in combination with inconclusive or negative results on JC virus detection in the cerebrospinal fluid. We discuss the challenges of applying current PML diagnostic criteria in asymptomatic natalizumab-associated PML patients and stress the need for specific diagnostic criteria and guidelines regarding managing these diagnostic dilemmas in order to facilitate an early and correct diagnosis of PML presumably leading to a better clinical outcome. [ABSTRACT FROM AUTHOR]

Patients' CD4 cell count was 446 cells/mm3, and HIV plasma viral load was 42800 copies/mL. Two months later, he interrupted the treatment with his own will then HIV plasma viral load increased; CD4 cell count decreased. Sir, Progressive multifocal leukoencephalopathy (PML) is a rare opportunistic infection of the central nervous system caused by John Cunningham virus (JCV). [Extracted from the article]