Paraneoplastic Calmodulin Kinase-Like Vesicle-Associated Protein (CAMKV) Autoimmune Encephalitis.

OBJECTIVES: To report an autoimmune paraneoplastic encephalitis characterized by immunoglobulin G (IgG) antibody targeting synaptic protein calmodulin kinase-like vesicle-associated (CAMKV). METHODS: Serum and cerebrospinal fluid (CSF) samples harboring unclassified antibodies on murine brain-based indirect immunofluorescence assay (IFA) were screened by human protein microarray. In 5 patients with identical cerebral IFA staining, CAMKV was identified as top-ranking candidate antigen. Western blots, confocal microscopy, immune-absorption, and mass spectrometry were performed to substantiate CAMKV specificity. Recombinant CAMKV-specific assays (cell-based [fixed and live] and Western blot) provided additional confirmation. RESULTS: Of 5 CAMKV-IgG positive patients, 3 were women (median symptom-onset age was 59 years; range, 53-74). Encephalitis-onset was subacute (4) or acute (1) and manifested with: altered mental status (all), seizures (4), hyperkinetic movements (4), psychiatric features (3), memory loss (2), and insomnia (2). Paraclinical testing revealed CSF lymphocytic pleocytosis (all 4 tested), electrographic seizures (3 of 4 tested), and striking MRI abnormalities in all (mesial temporal lobe T2 hyperintensities [all patients], caudate head T2 hyperintensities [3], and cortical diffusion weighted hyperintensities [2]). None had post-gadolinium enhancement. Cancers were uterine adenocarcinoma (3 patients: poorly differentiated or neuroendocrine-differentiated in 2, both demonstrated CAMKV immunoreactivity), bladder urothelial carcinoma (1), and non-Hodgkin lymphoma (1). Two patients developed encephalitis following immune checkpoint inhibitor cancer therapy (atezolizumab [1], pembrolizumab [1]). All treated patients (4) demonstrated an initial response to immunotherapy (corticosteroids [4], IVIG [2]), though 3 died from cancer. INTERPRETATION: CAMKV-IgG is a biomarker of immunotherapy-responsive paraneoplastic encephalitis with temporal and extratemporal features and uterine cancer as a prominent oncologic association. ANN NEUROL 2024.

An In-Depth Evaluation of Powdery Mildew Hosts Reveals One of the World's Most Common and Widespread Groups of Fungal Plant Pathogens.

Powdery mildews are highly destructive fungal plant pathogens that have a significant economic impact on both agricultural and ecological systems worldwide. The intricate relationship between powdery mildews and their host plants has led to cospeciation. In this study, we conducted an extensive evaluation of powdery mildew hosts to provide an updated understanding of the host ranges and distributions of these fungi. The "United States National Fungus Collections Fungus-Host Dataset" is the primary source of information for our analyses. The analysis of the dataset demonstrated the worldwide prevalence of powdery mildews; the data contained over 72,000 reports of powdery mildews, representing ∼8.7% of all host-fungal records. We have updated the taxonomy and nomenclature of powdery mildews. In total, powdery mildews infect ∼10,125 host taxa belonging to 205 families of flowering plants, which accounts for 1,970 genera in 200 countries across six continents. Furthermore, we estimate that powdery mildews infect approximately 2.9% of described angiosperm species. Our study underscores the need for regular updates on powdery mildew host information due to the continuously evolving taxonomy and the discovery of new host taxa. Since 1986, we estimate an additional 1,866 host taxa, 353 genera, and 36 families have been reported. Additionally, the identification of powdery mildew hosts provides valuable insights into the coevolutionary dynamics between the fungi and their plant hosts. Overall, this updated list provides valuable insights into the taxonomy and geographic distribution of powdery mildew species, which builds upon the previous work of Amano in 1986. Discerning the geographic spread and host range of economically significant plant pathogens is vital for biosecurity measures and identifying the origins and expansion of potentially harmful pathogens.

Avirulent Isolates of Penicillium chrysogenum to Control the Blue Mold of Apple Caused by P. expansum.

Blue mold is an economically significant postharvest disease of pome fruit that is primarily caused by Penicillium expansum. To manage this disease and sustain product quality, novel decay intervention strategies are needed that also maintain long-term efficacy. Biocontrol organisms and natural products are promising tools for managing postharvest diseases. Here, two Penicillium chrysogenum isolates, 404 and 413, were investigated as potential biocontrol agents against P. expansum in apple. Notably, 404 and 413 were non-pathogenic in apple, yet they grew vigorously in vitro when compared to the highly aggressive P. expansum R19 and Pe21 isolates. Whole-genome sequencing and species-specific barcoding identified both strains as P. chrysogenum. Each P. chrysogenum strain was inoculated in apple with the subsequent co-inoculation of R19 or Pe21 simultaneously, 3, or 7 days after prior inoculation with 404 or 413. The co-inoculation of these isolates showed reduced decay incidence and severity, with the most significant reduction from the longer establishment of P. chrysogenum. In vitro growth showed no antagonism between species, further suggesting competitive niche colonization as the mode of action for decay reduction. Both P. chrysogenum isolates had incomplete patulin gene clusters but tolerated patulin treatment. Finally, hygromycin resistance was observed for both P. chrysogenum isolates, yet they are not multiresistant to apple postharvest fungicides. Overall, we demonstrate the translative potential of P. chrysogenum to serve as an effective biocontrol agent against blue mold decay in apples, pending practical optimization and formulation.

Extensive intragenomic variation in the internal transcribed spacer region of fungi.

Fungi are among the most biodiverse organisms in the world. Accurate species identification is imperative for studies on fungal ecology and evolution. The internal transcribed spacer (ITS) rDNA region has been widely accepted as the universal barcode for fungi. However, several recent studies have uncovered intragenomic sequence variation within the ITS in multiple fungal species. Here, we mined the genome of 2414 fungal species to determine the prevalence of intragenomic variation and found that the genomes of 641 species, about one-quarter of the 2414 species examined, contained multiple ITS copies. Of those 641 species, 419 (∼65%) contained variation among copies revealing that intragenomic variation is common in fungi. We proceeded to show how these copies could result in the erroneous description of hundreds of fungal species and skew studies evaluating environmental DNA (eDNA) especially when making diversity estimates. Additionally, many genomes were found to be contaminated, especially those of unculturable fungi.

Genetic time traveling: sequencing old herbarium specimens, including the oldest herbarium specimen sequenced from kingdom Fungi, reveals the population structure of an agriculturally significant rust.

Sequencing herbarium specimens can be instrumental in answering ecological, evolutionary, and taxonomic inquiries. We developed a protocol for sequencing herbarium specimens of rust fungi (Pucciniales) and proceeded to sequence specimens ranging from 4 to 211 yr old from five different genera. We then obtained sequences from an economically important biological control agent, Puccinia suaveolens, to highlight the potential of sequencing herbarium specimens in an ecological sense and to evaluate the following hypotheses: (1) The population structure of a plant pathogen changes over time, and (2) introduced pathogens are more diverse in their native range. Our efforts resulted in sequences from 87 herbarium specimens that revealed a high level of diversity with a population structure that exhibited spatial-temporal patterns. The specimens sequenced from Europe showed more diversity than the ones from North America, uncovering an invasion pattern likely related to its European native host in North America. Additionally, to the best of our knowledge, the specimen from France collected in c. 1811 is the oldest herbarium specimen sequenced from kingdom Fungi. In conclusion, sequencing old herbarium specimens is an important tool that can be extrapolated to better understand plant-microbe evolution and to evaluate old type specimens to solidify the taxonomy of plant pathogenic fungi.

Phylogeny and taxonomy of the genera of Erysiphaceae, part 1: Golovinomyces.

Powdery mildews are a monophyletic group of obligate plant pathogenic fungi in the family Erysiphaceae. Powdery mildews are economically important in that they cause damage to many agriculturally significant crops and plants in ecologically important habitats. In this contribution, we introduce a new series of publications focusing on the phylogeny and taxonomy of this group, with an emphasis on specimens collected from North America. The first part of the series focuses on the genus Golovinomyces and includes a section detailing the powdery mildew species concept. We conducted analyses of Golovinomyces spp. with available rDNA sequence data from GenBank and supplemented the data set with rDNA (ITS, 28S, IGS) as well as protein-coding (GAPDH) data from 94 North American collections. Many of the species evaluated are included in phylogenetic and morphological analyses for the first time, including the American species G. americanus, G. brunneopunctatus, G. californicus, G. greeneanus, G. hydrophyllacearum, and G. sparsus. A special emphasis was placed on acquiring ex-type or ex-epitype sequences or presenting reference sequences for phylogenetic-taxonomic purposes. Three new species, G. eurybiarum, G. galiorum, and G. malvacearum, are described, and the new combinations G. fuegianus, G. mutisiae, and G. reginae are introduced. Ex-holotype sequences of Erysiphe sparsa (≡ G. sparsus) reveal that it should be reduced to synonymy with G. ambrosiae, and ex-epitype sequences of G. valerianae reveal that it should be reduced to synonymy with G. orontii. Multiple epitypes are designated with ex-epitype sequences.

Phylogeny and taxonomy of the genera of Erysiphaceae, part 2: Neoerysiphe.

The second contribution to a new series devoted to the phylogeny and taxonomy of powdery mildews is presented. An overview of Neoerysiphe species is given, including references to ex-type sequences or, if unavailable, representative reference sequences for phylogenetic-taxonomic purposes are provided. The new species N. stachydis is described, and Striatoidium jaborosae is reduced to synonymy with Neoerysiphe macquii. Epitypes with ex-epitype sequences are designated for Alphitomorpha ballotae, A. labiatarum, Erysiphe galii, E. chelones, and E. galeopsidis. Based on phylogenetic analyses, it has been demonstrated that Neoerysiphe cumminsiana is confined to its type host, Roldana hartwegii (= Senecio seemannii), and other North and South American parasites on Asteraceae hosts, previously assigned to this species, pertain to N. macquii. The first record of N. macquii from Europe (Germany) on cultivated Bidens aurea was confirmed by sequencing. Sequence analysis of type material of N. rubiae reveals that this species should be excluded from Neoerysiphe; however, the true affinity of this taxon is not yet clear.

More than a Virulence Factor: Patulin Is a Non-Host-Specific Toxin that Inhibits Postharvest Phytopathogens and Requires Efflux for Penicillium Tolerance.

Mycotoxin contamination is a leading cause of food spoilage and waste on a global scale. Patulin, a mycotoxin produced by Penicillium spp. during postharvest pome fruit decay, causes acute and chronic effects in humans, withstands pasteurization, and is not eliminated by fermentation. While much is known about the impact of patulin on human health, there are significant knowledge gaps concerning the effect of patulin during postharvest fruit-pathogen interactions. Application of patulin on six apple cultivars reproduced some blue mold symptoms that were cultivar-independent and dose-dependent. Identical symptoms were also observed in pear and mandarin orange. Six Penicillium isolates exposed to exogenous patulin exhibited delayed germination after 24 h, yet all produced viable colonies in 7 days. However, four common postharvest phytopathogenic fungi were completely inhibited by patulin during conidial germination and growth, suggesting the toxin is important for Penicillium to dominate the postharvest niche. Using clorgyline, a broad-spectrum efflux pump inhibitor, we demonstrated that efflux plays a role in Penicillium auto-resistance to patulin during conidial germination. The work presented here contributes new knowledge of patulin auto-resistance, its mode of action, and inhibitory role in fungal-fungal interactions. Our findings provide a solid foundation to develop toxin and decay mitigation approaches.

Neurosarcoidosis: Pathophysiology, Diagnosis, and Treatment.

Although often regarded as a protean illness with myriad clinical and imaging manifestations, neurosarcoidosis typically presents as recognizable syndromes that can be approached in a rational, systematic fashion. Understanding of neurosarcoidosis has progressed significantly in recent years, including updated diagnostic criteria and advances in treatment. The diagnosis of neurosarcoidosis is established by the clinical syndrome, imaging and histopathological findings, and exclusion of other causes. Mounting evidence supports the use of tumor necrosis factor inhibitors as an important addition to the therapeutic armamentarium, along with glucocorticoids and steroid-sparing cytotoxic immunosuppressants. In this narrative review, we summarize recent advances in the diagnosis and treatment of neurosarcoidosis.

Infections of the Spine and Spinal Cord.

PURPOSE OF REVIEW: Infections of the spine and spinal cord are associated with a high risk of morbidity and mortality and, therefore, require prompt clinical recognition, efficient diagnostic evaluation, and interdisciplinary treatment. This article reviews the pathophysiology, epidemiology, clinical manifestations, diagnosis, and treatment of infections of the spine and spinal cord to help practicing clinicians recognize, evaluate, and manage patients with such infections. RECENT FINDINGS: Aging of the population, increasing use of immunosuppressive medications, and other factors have contributed to increasing rates of spinal infections. Although the most common agents responsible for spinal infections remain bacteria and viruses, fungal infections occur in individuals who are immunocompromised, and parasitic infections are common in endemic regions, but patterns are in evolution with migration and climate change. Recent outbreaks of acute flaccid myelitis in children have been associated with enteroviruses A71 and D68. SUMMARY: Infections of the spine and spinal cord can be challenging to diagnose, requiring a thorough history and neurologic examination, laboratory studies of serum and CSF, neuroimaging (particularly MRI), and, in some instances, biopsy, to establish a diagnosis and treatment regimen. Interdisciplinary management including collaboration with experts in internal medicine, infectious disease, and neurosurgery is important to improve clinical outcomes.

An Analysis of Postharvest Fungal Pathogens Reveals Temporal-Spatial and Host-Pathogen Associations with Fungicide Resistance-Related Mutations.

Fungicides are the primary tools to control a wide range of postharvest fungal pathogens. Fungicide resistance is a widespread problem that has reduced the efficacy of fungicides. Resistance to FRAC-1 (Fungicide Resistance Action Committee-1) chemistries is associated with mutations in amino acid position 198 in the ß-tubulin gene. In our study, we conducted a meta-analysis of ß-tubulin sequences to infer temporal, spatial, plant host, and pathogen genus patterns of fungicide resistance in postharvest fungal pathogens. In total, data were acquired from 2,647 specimens from 12 genera of fungal phytopathogens residing in 53 countries on >200 hosts collected between 1926 and 2020. The specimens containing a position 198 mutation were globally distributed in a variety of pathosystems. Analyses showed that there are associations among the mutation and the year an isolate was collected, the pathogen genus, the pathogen host, and the collection region. Interestingly, fungicide-resistant ß-tubulin genotypes have been in a decline since their peak between 2005 and 2009. FRAC-1 fungicide usage data followed a similar pattern in that applications have been in a decline since their peak between 1997 and 2003. The data show that, with the reduction of selection pressure, FRAC-1 fungicide resistance in fungal populations will decline within 5 to 10 years. Based on this line of evidence, we contend that a ß-tubulin position 198 mutation has uncharacterized fitness cost(s) on fungi in nature. The compiled dataset can inform end users on the regions and hosts that are most prone to contain resistant pathogens and assist decisions concerning fungicide resistance management strategies.

Meningoencephalitis due to Spotted Fever Rickettsioses, Including Rocky Mountain Spotted Fever.

BACKGROUND: The spotted fever rickettsioses (SFR), including Rocky Mountain spotted fever, are tick-borne infections with frequent neurologic involvement. High morbidity and mortality make early recognition and empiric treatment critical. Most literature on SFR meningoencephalitis predates widespread magnetic resonance imaging (MRI) utilization. To better understand the contemporary presentation and outcomes of this disease, we analyzed clinical and radiographic features of patients with SFR meningoencephalitis. METHODS: Patients were identified through hospital laboratory-based surveillance or through the Tennessee Unexplained Encephalitis Study. Cases meeting inclusion criteria underwent medical records review and, when available, independent review of the neuroimaging. RESULTS: Nineteen cases (11 children, 8 adults) met criteria for SFR meningoencephalitis. Rash was significantly more common in children than adults (100% vs 50%, respectively), but other clinical features were similar between the 2 groups. Cerebrospinal fluid pleocytosis and protein elevation were each seen in 87.5% of cases, and hypoglycorrhachia was present in 18.8% of cases. The "starry sky" sign (multifocal, punctate diffusion restricting or T2 hyperintense lesions) was seen on MRI in all children, but no adults. Ninety percent of patients required intensive care unit admission and 39% were intubated. Outcomes were similar between adults and children, with only 46% making a complete recovery by the time of discharge. CONCLUSIONS: SFR meningoencephalitis is a life-threatening infection. The clinical presentation varies between adults and children based on the presence of rash and brain MRI findings. The starry sky sign was ubiquitous in children and should prompt consideration of empiric treatment for SFR when present.

Multiple sclerosis and sarcoidosis: A case for coexistence.

BACKGROUND: Patients with biopsy-proven systemic sarcoidosis who develop a chronic CNS disorder are often presumed to have neurosarcoidosis (NS), however, the possibility of comorbid neurologic disease, such as MS, must be considered if presentation and course are not typical for NS. METHODS: Retrospective chart review across 4 academic MS centers was undertaken to identify patients with diagnosis of MS (2017 McDonald criteria) and biopsy-confirmed extraneural sarcoidosis. Data were abstracted from each chart using a case report form that systematically queried for demographic, clinical, and paraclinical characteristics relevant to NS and MS. RESULTS: Ten patients met our inclusion criteria (mean age 47.7 [±5.9] years; 80% female). Noncaseating granulomas consistent with sarcoidosis were found on biopsy in all cases (lung 7/10, mediastinum 2/10, liver 1/10, spleen 1/10, and skin 1/10). Diagnosis of MS was based on clinical history of MS-like relapses and MRI findings characteristic of demyelination and typical disease evolution during follow-up (average of 7 years). No patient developed features of NS that could be considered a "red flag" against the diagnosis of MS (such as meningeal enhancement, hydrocephalus, and pituitary involvement). All patients were treated with disease-modifying therapy for MS. CONCLUSIONS: We propose a rational diagnostic approach to patients with sarcoidosis who may have comorbid MS. When the clinical picture is equivocal, the presence of multiple "MS-typical lesions" and the absence of any "NS-typical lesions" on MRI favor diagnosis of MS. Close follow-up is required to ascertain whether clinical and radiologic disease evolution and response to MS therapies conform to the proposed diagnosis of MS.

Emergency Evaluation and Management of Encephalitis and Myelitis in Adults.

Infection of the central nervous system is often a life-threatening emergency. In many cases, the clinician faces an unknown pathogen and must rely upon clinical acumen and a thorough, systematic diagnostic investigation to establish a diagnosis and initiate appropriate treatment. Because patients typically present with a syndrome, such as temporal lobe encephalitis, rather than a known pathogen (e.g., herpes simplex virus 1 encephalitis), we describe diagnostic considerations in the context of their neuroanatomic tropisms and patterns of disease. This paradigm reflects the challenges clinicians face; however, tropisms are not absolute, patterns of disease are not specific, and this approach does not obviate the need for empirical treatment while a systematic diagnostic investigation is underway. Specific treatment is available for many infectious agents, including bacterial, fungal, and parasitic pathogens, as well as the herpesviruses. In cases with no specific treatment, clinicians must strive to establish the diagnosis (and thereby spare unneeded treatment), anticipate and recognize complications and pitfalls, and initiate appropriate supportive care, all of which are best achieved with a well-prepared multidisciplinary team.

An Overview of Autoimmune and Paraneoplastic Encephalitides.

The understanding of the manifestations, mechanisms, and management of autoimmune encephalitis has expanded dramatically in recent decades. Immune-mediated encephalitides are comparable in incidence and prevalence to infectious etiologies, and are associated with significant morbidity, especially when there is a delay in recognition and treatment. As such, clinicians from many specialties must develop a functional understanding of these disorders. Herein we provide an overview of the autoimmune and paraneoplastic encephalitides, including those associated with either intracellular or cell surface/synaptic neuronal autoantibodies. After briefly reviewing the current understanding of the pathobiology of autoimmune encephalitis, we combine a neuroanatomical approach with specific antibody syndromes to provide the reader with a clinically relevant review of these disorders. The clinical manifestations, diagnosis, and management of autoimmune encephalitis are reviewed, with an emphasis on clinical relevance. We also introduce updates in the field, including autoimmune encephalitis associated with novel cancer immunotherapies, infectious triggers of autoimmune encephalitis, and autoimmune encephalitis with demyelinating overlap syndromes.

Effectiveness of alternative dose fingolimod for multiple sclerosis.

BACKGROUND: Fingolimod is a daily oral medication used to treat relapsing multiple sclerosis (MS). Clinicians often adopt less frequent dosing for patients with profound drug-induced lymphopenia or other adverse events. Data on the effectiveness of alternate dose fingolimod are limited. METHODS: We conducted a multicenter, retrospective, observational study at 14 sites and identified 170 patients with MS taking alternate doses of fingolimod for ≥1 month. Clinical and radiologic outcomes were collected and compared during daily and alternate fingolimod dosing. RESULTS: Profound lymphopenia (77%), liver function abnormalities (9%), and infections (7%) were the most common reasons for patients to switch to alternate fingolimod dosing. The median follow-up was 12 months on daily dose and 14 months on alternate dose. Most patients (64%) took fingolimod every other day during alternate dosing. Disease activity was similar on alternate dose compared to daily dose: annualized relapse rate was 0.1 on daily dose vs 0.2 on alternate dose (p = 0.25); proportion of patients with contrast-enhancing MRI lesions was 7.6% on daily vs 9.4% on alternate (p = 0.55); proportion of patients with cumulative MS activity (clinical and radiologic disease) was 13.5% on daily vs 18.2% on alternate (p = 0.337). Patients who developed contrast-enhancing lesions while on daily dose were at higher risk for breakthrough disease while on alternate dose fingolimod (odds ratio 11.4, p < 0.001). CONCLUSIONS: These data support the clinical strategy of alternate dosing of fingolimod in patients with good disease control but profound lymphopenia or other adverse events while on daily dose. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for patients with MS on daily dose fingolimod with adverse events, alternate dose fingolimod is associated with disease activity similar to daily dose fingolimod.

Wearable biosensors to monitor disability in multiple sclerosis.

PURPOSE OF REVIEW: Biosensors capable of measuring physiologic and kinetic parameters associated with disability are being applied to the study of people with multiple sclerosis (MS). We review the use of biosensors in people with MS with an emphasis on measuring/monitoring disability and understanding knowledge gaps between biosensor data and clinical care. RECENT FINDINGS: Accelerometers are available to the public and may be able to help the clinician understand a patient's degree of disability. Further studies with wearable biosensors capable of measuring other physiologic features, such as vital signs, are needed and are likely to contribute to our understanding of MS. SUMMARY: Wearable biosensors can improve our understanding of disability, response to treatment, and natural history of MS.