Eight patients with progressive multifocal leukoencephalopathy associated with chronic lymphocytic leukemia, HIV infection, lymphoma, or idiopathic lymphopenia received pembrolizumab. Five patients ...had clinical improvement or stabilization of PML, reduction in lesion size on MRI, and decreased JC viral load. Three showed no clinical benefit.
The diagnosis of central nervous system (CNS) infections is crucial for preventing long-term damage. However, it poses several challenges, including the need for a quick and accurate diagnosis. In a ...recent study, Cortes et al analyzed 496 cerebrospinal fluid (CSF) samples using a commercially available nested PCR assay called BioFire FilmArray. This assay is designed to detect 14 pathogens, including bacteria, viruses, and fungi. The authors found that 88 samples tested positive, with enterovirus being the most common pathogen detected. However, the assay has limitations, such as a high false positive rate and the lack of confirmatory tests for viral pathogens. Additionally, the assay does not cover all common causes of meningoencephalitis. Other techniques, such as next-generation sequencing, should be considered for detecting infectious agents, especially in cases where viral infections are suspected. Cost is also a limiting factor for these technologies. While the BioFire panel may be helpful in resource-limited settings, a cost-benefit analysis is necessary. Overall, early and accurate diagnosis of CNS infections is crucial for effective management and cost savings in healthcare.
Background:
Myalgic encephalomyelitis/chronic fatigue syndrome is characterized by persistent and disabling fatigue, exercise intolerance, cognitive difficulty, and musculoskeletal/joint pain. ...Post–exertional malaise is a worsening of these symptoms after a physical or mental exertion and is considered a central feature of the illness. Scant observations in the available literature provide qualitative assessments of post–exertional malaise in patients with myalgic encephalomyelitis/chronic fatigue syndrome. To enhance our understanding, a series of outpatient focus groups were convened.
Methods:
Nine focus groups totaling 43 patients who reported being diagnosed with myalgic encephalomyelitis/chronic fatigue syndrome were held between November 2016 and August 2019. Focus groups queried post–exertional malaise in daily life and participants' retrospective memory of post–exertional malaise that followed an exercise provocation with a cardiopulmonary exercise test. Data analysis followed the grounded theory method to systematically code and categorize the data to find meaningful patterns. A qualitative software package was used to move text into categories during data coding.
Results:
A wide range of symptoms were attributed to exertion both in daily lives and following cardiopulmonary exercise testing. While three core symptoms emerged (exhaustion, cognitive difficulties, and neuromuscular complaints), participants' descriptions were notable for their unique individual variations. Of 18 participants who responded to questions centered around symptoms following a cardiopulmonary exercise test, 17 reported that symptoms started within 24 h and peaked in severity within 72 h following the cardiopulmonary exercise test. Patients described post–exertional malaise as interfering with their ability to lead a “normal” life.
Conclusion:
The experience of post–exertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome varies greatly between individuals and leads to a diminished quality of life. myalgic encephalomyelitis/chronic fatigue syndrome patients describe post–exertional malaise as all-encompassing with symptoms affecting every part of the body, difficult to predict or manage, and requiring complete bedrest to fully or partially recover. Given the extensive variability in patients, further research identifying subtypes of post–exertional malaise could lead to better targeted therapeutic options.
The current paper provides the most detailed description of the various neurological manifestations in this population. The authors show that even in the acute phase, neurological complications can ...involve the entire neuraxis. which includes peripheral neuropathies and rhabdomyolysis (Table l)8. The number of neurological complications of SARS-CoV-2 is steadily increasing in their hospital on a daily basis, clearly an ominous sign. These complications are being recognized in the acute phase of the illness. However, there are additional post-viral syndromes affecting the nervous system, including dysautonomiaq and persistent fatigue. exercise intolerance, and malaise that many patients are experiencing months after recovering from the acute illness. Many of these patients had only minimal respiratory symptoms. The long-term consequences of these manifestations can have a major impact on all aspects of health care, with major socioeconomic consequences. Hence, the neurological manifestations should be front and center to the disease.
The role of human endogenous retroviruses (HERVs) in disease pathogenesis is unclear. We show that HERV-K is activated in a subpopulation of patients with sporadic amyotrophic lateral sclerosis (ALS) ...and that its envelope (env) protein may contribute to neurodegeneration. The virus was expressed in cortical and spinal neurons of ALS patients, but not in neurons from control healthy individuals. Expression of HERV-K or its env protein in human neurons caused retraction and beading of neurites. Transgenic animals expressing the env gene developed progressive motor dysfunction accompanied by selective loss of volume of the motor cortex, decreased synaptic activity in pyramidal neurons, dendritic spine abnormalities, nucleolar dysfunction, and DNA damage. Injury to anterior horn cells in the spinal cord was manifested by muscle atrophy and pathological changes consistent with nerve fiber denervation and reinnervation. Expression of HERV-K was regulated by TAR (trans-activation responsive) DNA binding protein 43, which binds to the long terminal repeat region of the virus. Thus, HERV-K expression within neurons of patients with ALS may contribute to neurodegeneration and disease pathogenesis.
Summary Background Treatment of multiple sclerosis with natalizumab is complicated by rare occurrence of progressive multifocal leukoencephalopathy (PML). Between July, 2006, and November, 2009, ...there were 28 cases of confirmed PML in patients with multiple sclerosis treated with natalizumab. Assessment of these clinical cases will help to inform future therapeutic judgments and improve the outcomes for patients. Recent developments The risk of PML increases with duration of exposure to natalizumab over the first 3 years of treatment. No new cases occurred during the first two years of natalizumab marketing but, by the end of November, 2009, 28 cases had been confirmed, of which eight were fatal. The median treatment duration to onset of symptoms was 25 months (range 6–80 months). The presenting symptoms most commonly included changes in cognition, personality, and motor performance, but several cases had seizures as the first clinical event. Although PML has developed in patients without any previous use of disease-modifying therapies for multiple sclerosis, previous therapy with immunosuppressants might increase risk. Clinical diagnosis by use of MRI and detection of JC virus in the CSF was established in all but one case. Management of PML has routinely used plasma exchange (PLEX) or immunoabsorption to hasten clearance of natalizumab and shorten the period in which natalizumab remains active (usually several months). Exacerbation of symptoms and enlargement of lesions on MRI have occurred within a few days to a few weeks after PLEX, indicative of immune reconstitution inflammatory syndrome (IRIS). This syndrome seems to be more common and more severe in patients with natalizumab-associated PML than it is in patients with HIV-associated PML. Where next? Diagnosis of natalizumab-associated PML requires optimised clinical vigilance, reliable and sensitive PCR testing of the JC virus, and broadened criteria for recognition of PML lesions by use of MRI, including contrast enhancement. Optimising the management of IRIS reactions will be needed to improve outcomes. Predictive markers for patients at risk for PML must be sought. It is crucial to monitor the risk incurred during use of natalizumab beyond 3 years.
Chronic immune activation is a major complication of antiretroviral therapy (ART) for HIV infection and can cause a devastating immune reconstitution inflammatory syndrome (IRIS) in the brain. The ...mechanism of T-cell activation in this population is not well understood. We found HIV-Tat protein and IL-17–expressing mononuclear cells in the brain of an individual with IRIS. Tat was also present in the CSF of individuals virologically controlled on ART. Hence we examined if Tat protein could directly activate T cells. Tat transcriptionally dysregulated 94 genes and induced secretion of 11 cytokines particularly activation of IL-17 signaling pathways supporting the development of a proinflammatory state. Tat increased IL-17 transcription and secretion in T cells. Tat entered the T cells rapidly by clathrin-mediated endocytosis and localized to both the cytoplasm and the nucleus. Tat activated T cells through a nonclassical pathway dependent upon vascular endothelial growth factor receptor-2 and downstream secondary signaling pathways but independent of the T-cell receptor. However, Tat stimulation of T cells did not induce T-cell proliferation but increased viral infectivity. This study demonstrates Tat’s role as a virulence factor, by driving T-cell activation and contributing to IRIS pathophysiology. This supports the necessity of an anti-Tat therapy in conjunction with ART and identifies multiple targetable pathways to prevent Tat-mediated T-cell activation.
Despite the repetitive association of endogenous retroviruses in human disease, the mechanisms behind their pathological contributions remain to be resolved. Here we discuss how neuronal human ...endogenous retrovirus-K (HERV-K) expression in human immunodeficiency virus (HIV)-infected individuals is a distinct pathological aspect of HIV-associated neurological conditions, such as HIV encephalitis and HIV-associated neurocognitive disorders. Enhanced neuronal HERV-K levels were observed in the majority of HIV-infected individuals, and to a higher degree in brain tissue marked by HIV replication. Moreover, we highlight an important neuropathological overlap between amyotrophic lateral sclerosis and HIV encephalitis, that being the formation of neurotoxic TDP-43 deposits in neurons. Herein, we argue for enhanced transdisciplinary research in the field of ERV biology, using an example of how HERV-K expression has novel mechanistic and therapeutic implications for HIV neuropathology.
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