Public health trends in neurologically relevant infections: a global perspective.

Neuroinfectious diseases represent a growing threat to public health globally. Infections of the central nervous system remain challenging to diagnose and treat, partially driven by the fact that a high proportion of emerging pathogens are capable of causing neurological disease. Many of the trends driving the emergence of novel pathogens, including climate change, ecological degradation, urbanization, and global travel, have accelerated in recent years. These circumstances raise concern for the potential emergence of additional pathogens of pandemic potential in the coming years, necessitating a stronger understanding of the forces that give rise to the emergence and spread of neuroinvasive pathogens and a commitment to public health infrastructure to identify and treat these diseases. In this review, we discuss the clinical and epidemiological features of three types of emerging neuroinvasive pathogens of significant public health consequences that are emblematic of key ongoing trends in global health. We first discuss dengue viruses in the context of climate change, considering the environmental factors that allow for the expansion of the geographic range and seasonal population of the viruses' vector. We then review the rising prevalence of fungal meningitis secondary to medical tourism, a trend representative of the highly globalized nature of modern healthcare. Lastly, we discuss the increasing prevalence of antibiotic-resistant neurological infections driven by the intersection of antibiotic overuse in medical and agricultural settings. Taken together, the rising prevalence of these conditions necessitates a recommitment to investment in public health infrastructure focused on local and global infectious disease surveillance coupled with ongoing development of novel therapeutics and vaccines for emerging pathogens. Such emerging threats also obviate the need to address the root causes driving the emergence of novel infectious diseases, including a sustained effort to address anthropogenic climate change and environmental degradation.

Public health trends in neurologically-relevant infections: a global perspective Globally, infections that impact the central nervous system, referring to the brain and spinal cord, are of significant public health concern. In the medical setting, these infections are challenging to diagnose both because of the overall difficulty of diagnosing any neurological infection but also because many infections of the nervous system are caused by newly emerging pathogens that lack reliable tests for diagnosis. Some of the trends contributing to emergence of new pathogens are the result of increasing globalization combined with climate change, destruction of the natural environment, increased growth of cities, and global travel. In our review, we discuss three types of infections that can affect the nervous system in the context of these trends. We discuss dengue viruses, which are spread by mosquitoes, in the context of climate change that increases the range at which dengue-carrying mosquitoes can live. We also discuss fungal meningitis, referring to fungal infections of the lining of the brain, resulting from patients traveling globally for surgical procedures. We lastly discuss the increase in neurological infections resistant to antibiotic treatment, which has resulted from overuse of antibiotics in medical and agricultural settings. As a whole, these trends show the need to invest further in public health systems at monitor for newly emerging diseases, as well as a commitment to developing vaccines and treatments for these diseases. The threats of these pathogens also make clear the need to address the underlying causes leading to their emergence and spread, including climate change and environmental degradation.

Canadian Consensus Guidelines for the Diagnosis and Treatment of Autoimmune Encephalitis in Adults.

Autoimmune encephalitis is increasingly recognized as a neurologic cause of acute mental status changes with similar prevalence to infectious encephalitis. Despite rising awareness, approaches to diagnosis remain inconsistent and evidence for optimal treatment is limited. The following Canadian guidelines represent a consensus and evidence (where available) based approach to both the diagnosis and treatment of adult patients with autoimmune encephalitis. The guidelines were developed using a modified RAND process and included input from specialists in autoimmune neurology, neuropsychiatry and infectious diseases. These guidelines are targeted at front line clinicians and were created to provide a pragmatic and practical approach to managing such patients in the acute setting.

Identification of SKOR2 IgG as a novel biomarker of paraneoplastic neurologic syndrome.

Introduction: The development of new autoantigen discovery techniques, like programmable phage immunoprecipitation sequencing (PhIP-Seq), has accelerated the discovery of neural-specific autoantibodies. Herein, we report the identification of a novel biomarker for paraneoplastic neurologic syndrome (PNS), Sloan-Kettering-Virus-Family-Transcriptional-Corepressor-2 (SKOR2)-IgG, utilizing PhIP-Seq. We have also performed a thorough clinical validation using normal, healthy, and disease/cancer control samples. Methods: Stored samples with unclassified staining at the junction of the Purkinje cell and the granule cell layers were analyzed by PhIP-Seq for putative autoantigen identification. The autoantigen was confirmed by recombinant antigen-expressing cell-based assay (CBA), Western blotting, and tissue immunofluorescence assay colocalization. Results: PhIP-Seq data revealed SKOR2 as the candidate autoantigen. The target antigen was confirmed by a recombinant SKOR-2-expressing, and cell lysate Western blot. Furthermore, IgG from both patient samples colocalized with a commercial SKOR2-specific IgG on cryosections of the mouse brain. Both SKOR2 IgG-positive patients had central nervous system involvement, one presenting with encephalitis and seizures (Patient 1) and the other with cognitive dysfunction, spastic ataxia, dysarthria, dysphagia, and pseudobulbar affect (Patient 2). They had a refractory progressive course and were diagnosed with adenocarcinoma (Patient 1: lung, Patient 2: gallbladder). Sera from adenocarcinoma patients without PNS (n=30) tested for SKOR2-IgG were negative. Discussion: SKOR2 IgG represents a novel biomarker for PNS associated with adenocarcinoma. Identification of additional SKOR2 IgG-positive cases will help categorize the associated neurological phenotype and the risk of underlying malignancy.

Diagnosing viral encephalitis and emerging concepts.

PURPOSE OF REVIEW: This review offers a contemporary clinical approach to the diagnosis of viral encephalitis and discusses recent advances in the field. The neurologic effects of coronaviruses, including COVID-19, as well as management of encephalitis are not covered in this review. RECENT FINDINGS: The diagnostic tools for evaluating patients with viral encephalitis are evolving quickly. Multiplex PCR panels are now in widespread use and allow for rapid pathogen detection and potentially reduce empiric antimicrobial exposure in certain patients, while metagenomic next-generation sequencing holds great promise in diagnosing challenging and rarer causes of viral encephalitis. We also review topical and emerging infections pertinent to neuroinfectious disease practice, including emerging arboviruses, monkeypox virus (mpox), and measles. SUMMARY: Although etiological diagnosis remains challenging in viral encephalitis, recent advances may soon provide the clinician with additional tools. Environmental changes, host factors (such as ubiquitous use of immunosuppression), and societal trends (re-emergence of vaccine preventable diseases) are likely to change the landscape of neurologic infections that are considered and treated in clinical practice.

Severe Arboviral Neuroinvasive Disease in Patients on Rituximab Therapy: A Review.

With increasing use of rituximab and other B-cell depleting monoclonal antibodies for multiple indications, infectious complications are being recognized. We summarize clinical findings of patients on rituximab with arboviral diseases identified through literature review or consultation with the Centers for Disease Control and Prevention. We identified 21 patients on recent rituximab therapy who were diagnosed with an arboviral disease caused by West Nile, tick-borne encephalitis, eastern equine encephalitis, Cache Valley, Jamestown Canyon, and Powassan viruses. All reported patients had neuroinvasive disease. The diagnosis of arboviral infection required molecular testing in 20 (95%) patients. Median illness duration was 36 days (range, 12 days to 1 year), and 15/19 (79%) patients died from their illness. Patients on rituximab with arboviral disease can have a severe or prolonged course with an absence of serologic response. Patients should be counseled about mosquito and tick bite prevention when receiving rituximab and other B-cell depleting therapies.

Neurology of Acute Viral Infections.

As specialists in acute neurology, neurohospitalists are often called upon to diagnose and manage acute viral infections affecting the nervous system. In this broad review covering the neurology of several acute viral infections, our aim is to provide key diagnostic and therapeutic pearls of practical use to the busy neurohospitalist. We will review acute presentations, diagnosis, and treatment of human herpesviruses, arboviruses, enteroviruses, and some vaccine-preventable viruses. The neurological effects of coronaviruses, including COVID-19, are not covered in this review.

Enterovirus A71 causing meningoencephalitis and acute flaccid myelitis in a patient receiving rituximab.

We present the case of a young woman being treated with rituximab for rheumatoid arthritis who developed a severe enteroviral meningoencephalitis and acute flaccid myelitis (AFM). Cerebrospinal fluid (CSF) and stool reverse transcription-polymerase chain reaction (RT-PCR) testing confirmed the diagnosis and additional sequencing studies performed at the CDC further characterized the enterovirus as enterovirus A71 (EV-A71). After treatment with intravenous immunoglobulin (IVIg) and fluoxetine (based on previous reports of possible efficacy) the patient experienced a remarkable improvement over time. This case highlights the importance of considering enteroviral infection in patients treated with rituximab, depicts a possible clinical course of enteroviral meningoencephalitis and AFM, and illustrates the importance of testing multiple sites for enterovirus infection (CSF, stool, nasopharyngeal swab, blood). Here we present the case with a brief review of the literature pertaining to EV-A71.

Glial fibrillary acidic protein (GFAP) associated autoimmune meningoencephalitis in a patient receiving nivolumab.

Immune checkpoint inhibitors (ICIs) represent a major development in cancer treatment, allowing for improved survival and disease control in an expanding number of cancer types. Due to their mechanism of disrupting immunologic homeostasis, ICIs are frequently associated with adverse effects, termed immune related adverse effects (irAE). These side effects can affect any organ system, including the central and peripheral nervous systems. We present a case of a 47 year old man with stage IIIc metastatic melanoma who received 3 cycles of nivolumab (a monoclonal antibody inhibitor of programmed cell death protein 1 (PD-1)). After completing the third cycle, he presented with a meningoencephalitis clinical picture with an inflammatory cerebrospinal fluid (CSF) and normal MRI. He was found to have a positive anti-glial fibrillary acidic protein (GFAP) autoantibody in his CSF by immunofluorescent assay (IFA) and cell based assay (CBA) which confirmed a diagnosis of anti-GFAP autoimmune encephalitis. He was treated with immunotherapy and made a full recovery. In this report, we present the first reported case of anti-GFAP autoimmune encephalitis associated with ICI therapy and provide a brief review of the literature.

Usutu virus disease: a potential problem for North America?

Usutu virus is an emerging mosquito-borne flavivirus initially identified in South Africa in 1959 that is now circulating throughout parts of Africa, Europe, and the Middle East. It is closely related to West Nile virus, and has similar vectors, amplifying bird hosts, and epidemiology. Usutu virus infection can occur in humans and may be asymptomatic or cause systemic (e.g., fever, rash, and hepatitis) or neuroinvasive (e.g., meningitis and encephalitis) disease. Given few reported cases, the full clinical spectrum is not known. No anti-viral treatment is available, but it can be largely prevented by avoiding mosquito bites. Because of similar mosquitoes, birds, and climate to Europe, the potential for introduction to North America is possible.