Time to Confirmed Neuroinfectious Diagnoses: Diagnostic Testing and Resource Allocation.

Background and Objectives: In a retrospective study evaluating the diagnostic approach of definitive neurological infections at a tertiary referral center, we assessed the time to diagnosis from presentation, number of diagnostic tests ordered, and modality of etiologic diagnosis. Methods: A total of 111 confirmed clinical cases of neurological infections from 2010-2018 were reviewed. Definitive neuroinfectious diagnoses were defined by positive cerebrospinal (CSF) polymerase chain reaction (PCR)/antigen, CSF culture, CSF antibody, serology, or pathology tests. Results: An etiologic diagnosis was determined at an average (SD) of 3.1 (5.9) days after presentation with an average (SD) of 27.7 (15.6) diagnostic tests ordered per workup.Viral neuro-infections were associated with lower intensive care unit (ICU) admission rates, shorter length of hospitalization, and fewer diagnostic tests ordered, as well as shorter time to definitive diagnosis (P < .05). Longer hospitalizations were associated with immunosuppression status regardless of infectious etiology (P < .001). Discussion: Given the high morbidity and mortality of neuroinfectious disease, specifically meningitis and encephalitis, efficient diagnostic testing is imperative to facilitate the most appropriate clinical course of action with special attention to the specific patient population.

Clinical and Diagnostic Features of West Nile Virus Neuroinvasive Disease in New York City.

West Nile virus (WNV) neuroinvasive disease (WNND) occurs in approximately 1 percent of WNV-infected patients and typically presents as encephalitis, meningitis, or acute flaccid paralysis (AFP). WNND remains a difficult inpatient diagnosis, creating significant challenges for prognostication and therapy selection. We characterized the clinical and diagnostic features of WNND cases at two major academic medical centers in New York City in routine clinical practice. We retrospectively reviewed the charts of thirty-six patients with WNND, including twenty-six encephalitis, four meningitis, and six AFP cases. The most common presenting symptoms were fever (86.1%) and gastrointestinal symptoms (38.9%) in addition to altered mental status (72.2%), lethargy (63.9%), gait disturbances (46.2%), and headache (44.4%). Fourteen (48.3%) patients displayed acute magnetic resonance imaging (MRI) findings, particularly T2 hyperintensities in the bilateral thalami, brainstem, and deep white matter. New York State Department of Health WNV CSF IgM testing was utilized for diagnosis in 58.3% of patients; however, just 38.1% had the result by discharge, compared to 85.6% of those who underwent serum IgM testing. The median length of stay was 13.5 days, 38.9% were intubated, and three patients (8.9%) died during acute hospitalization. Our findings underscore the morbidity, mortality, and diagnostic challenges of WNND, suggesting the potential utility of serum IgM testing in combination with confirmatory CSF testing to expedite diagnosis in the acute setting.

Neuroinfectious Diseases in Children: Pathophysiology, Outcomes, and Global Challenges.

Pathogens with affinity for the central nervous system (CNS) in children are diverse in their mechanisms of infecting and attacking the brain. Infections can reach the CNS via hematogenous routes, transneurally thereby avoiding the blood-brain barrier, and across mucosal or skin surfaces. Once transmission occurs, pathogens can wreak havoc both by direct action on host cells and via an intricate interplay between the protective and pathologic actions of the host's immune system. Pathogen prevalence varies depending on region, and susceptibility differs based on epidemiologic factors such as age, immune status, and genetics. In addition, some infectious diseases are monophasic, whereas others may lie dormant for years, thereby causing a dynamic effect on outcomes. Outcomes in survivors are highly variable for each particular pathogen and depend on the vaccination and immune status of the patient as well as the speed by which the patient receives evidence-based treatments. Given pathogens cause communicable diseases that can cause morbidity and mortality on a population level when spread, the burden is often the greatest and the outcomes the worst in low-resource settings. Here we will focus on the most common infections with a propensity to affect a child's brain, the pathologic mechanisms by which they do so, and what is known about the developmental outcomes in children who are affected by these infections.

Application of VirCapSeq-VERT and BacCapSeq in the diagnosis of presumed and definitive neuroinfectious diseases.

Unbiased high-throughput sequencing (HTS) has enabled new insights into the diversity of agents implicated in central nervous system (CNS) infections. The addition of positive selection capture methods to HTS has enhanced the sensitivity while reducing sequencing costs and the complexity of bioinformatic analysis. Here we report the use of virus capture-based sequencing for vertebrate viruses (VirCapSeq-VERT) and bacterial capture sequencing (BacCapSeq) in investigating CNS infections. Thirty-four samples were categorized: (1) patients with definitive CNS infection by routine testing; (2) patients meeting clinically the Brighton criteria (BC) for meningoencephalitis; (3) patients with presumptive infectious etiology highest on the differential. RNA extracts from cerebrospinal fluid (CSF) were used for VirCapSeq-VERT, and DNA extracts were used for BacCapSeq analysis. Among 8 samples from known CNS infections in group 1, VirCapSeq and BacCapSeq confirmed 3 expected diagnoses (42.8%), were negative in 2 (25%), yielded an alternative result in 1 (11.1%), and did not detect 2 expected negative pathogens. The confirmed cases identified HHV-6, HSV-2, and VZV while the negative samples included JCV and HSV-2. In groups 2 and 3, 11/26 samples (42%) were positive for at least one pathogen; however, 27% of the total samples (7/26) were positive for commensal organisms. No microbial nucleic acids were detected in negative control samples. HTS showed limited promise for pathogen identification in presumed CNS infectious diseases in our small sample. Before conducting larger-scale prospective studies to assess the clinical value of this novel technique, clinicians should understand the benefits and limitations of using this modality.

Application of VirCapSeq-VERT and BacCapSeq In the Diagnosis of Presumed and Definitive Neuroinfectious Diseases.

Background: Unbiased high-throughput sequencing (HTS) has enabled new insights into the diversity of agents implicated in central nervous system (CNS) infections. The addition of positive selection capture methods to HTS has enhanced the sensitivity while reducing sequencing costs and complexity of bioinformatic analysis. Here we report the use of virus capture based sequencing for vertebrate viruses (VirCapSeq-VERT) and bacterial capture sequencing (BacCapSeq) in investigating CNS infections. Design/Methods: Thirty-four samples were categorized: (1) Patients with definitive CNS infection by routine testing; (2) Patients meeting clinically Brighton Criteria (BC) for meningoencephalitis (3) Patients with presumptive infectious etiology highest on the differential. RNA extracts from cerebrospinal fluid (CSF) were used for VirCapSeq-VERT and DNA extracts were used for BacCapSeq analysis. Results: Among 8 samples from known CNS infections in group 1, VirCapSeq and BacCapSeq confirmed 3 expected diagnoses (42.8%), were negative in 2 (25%), yielded an alternative result in 1 (11.1%), and did not detect 2 expected negative pathogens. The confirmed cases identified HHV-6, HSV-2, and VZV while the negative samples included JCV and HSV-2. In groups 2 and 3,11/26 samples (42%) were positive for at least one pathogen, however 27% of the total samples (7/26) were positive for commensal organisms. No microbial nucleic acids were detected in negative control samples. Conclusions: HTS showed limited promise for pathogen identification in presumed CNS infectious diseases in our small sample. Before conducting larger-scale prospective studies to assess clinical value of this novel technique, clinicians should understand benefits and limitations of using this modality.

Neurology of Systemic Disease: Selected Topics with a Focus on Women.

Sex differences exist within the neurologic complications of systemic disease. To promote new avenues for prevention and develop novel therapeutics, we highlight the role of sex in differential outcomes to infectious disease and cardiac arrest and educate the reader in paraneoplastic presentations that may herald underlying malignancies in women.

An Autopsy Report of a Case with Cerebral Infarction Complicated by Coronavirus Disease 2019 Infection.

We herein report a case of cerebral infarct in a patient with coronavirus disease 2019 (COVID-19) infection who died of aspiration pneumonia. The postmortem examination of the brain revealed embolic infarct with negative findings on quantitative reverse transcription polymerase chain reaction (qRT-PCR) as well as immunohistochemistry to detect severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The systemic examination only revealed low copy numbers of SARS-CoV-2 in the bronchus. This is the first and so far only autopsy case of COVID-19 infection with pathologic and virologic findings of the postmortem brain in Japan.

Plasma Microbial Cell-Free DNA (CF-DNA) Next-Generation Sequencing in Diagnosing Intracranial Abscesses: Pathophysiology and a Scoping Review of the Literature.

Plasma microbial cell-free DNA (cf-DNA) from next-generation sequencing (NGS) provides improved sensitivity and specificity compared to standard microbial blood cultures. cf-DNA sequencing also has an improved turnaround time (TAT) and allows quicker commencement of antibiotics in life-threatening infections such as a brain abscess. Brain abscesses carry significant morbidity and mortality. Empiric treatment and management are critical in improving functional neurological outcomes. Reported here is the case of a severe central nervous system (CNS) infection with multiple ring-enhancing lesions seen throughout the cerebrum on magnetic resonance imaging (MRI). Standard microbial blood cultures were inconclusive and definitive identification of the pathogen was achieved through microbial cf-DNA NGS.  Brain abscesses develop in four distinct phases: early cerebritis, late cerebritis, early capsule formation, and late capsule formation. The pathogenesis of cerebral abscess involves direct parenchymal inflammation of the pathogen, the recruitment of inflammatory CNS cell types (microglia, inflammatory astrocytes, etc), and the chemotaxis of immune cells. cf-DNA is released into the bloodstream in response to pathogen opsonization and immune-mediated cell death. A scoping literature review includes cases of intracranial abscesses diagnosed via cf-DNA NGS.

Neuroinvasive West Nile Virus (WNV) Encephalitis With Anton Syndrome: Epidemiology and Pathophysiology Review.

The West Nile virus (WNV) belongs to the genus of flaviviruses and is known to cause irreversible neurologic deficits. Neuroinvasive WNV cases continue to be rare and have a higher prevalence in South America, Africa, and Asia. Here we report a 55-year-old female from North America who presented with acute-onset encephalopathy, fever, myalgias, and Anton syndrome. Neuroradiographic findings included diffuse white matter abnormalities of both cortical and subcortical structures and the patient was diagnosed with posterior reversible encephalopathy syndrome (PRES). Further workup revealed WNV antibodies in both cerebrospinal fluid (CSF) and serum. Management of WNV encephalitis continues to be poor and thus the patient was referred to a long-term care facility. Furthermore, Anton syndrome is a rare focal neurologic deficit that has never been previously associated with the WNV. This case aims to highlight the epidemiology of WNV in the United States, the mechanisms of WNV encephalitis, and an overview of Anton syndrome.

Neurocognitive screening in patients following SARS-CoV-2 infection: tools for triage.

BACKGROUND: Cognitive complaints are common in patients recovering from Coronavirus Disease 2019 (COVID-19), yet their etiology is often unclear. We assess factors that contribute to cognitive impairment in ambulatory versus hospitalized patients during the sub-acute stage of recovery. METHODS: In this cross-sectional study, participants were prospectively recruited from a hospital-wide registry. All patients tested positive for SARS-CoV-2 infection using a real-time reverse transcriptase polymerase-chain-reaction assay. Patients ≤ 18 years-of-age and those with a pre-existing major neurocognitive disorder were excluded. Participants completed an extensive neuropsychological questionnaire and a computerized cognitive screen via remote telemedicine platform. Rates of subjective and objective neuropsychological impairment were compared between the ambulatory and hospitalized groups. Factors associated with impairment were explored separately within each group. RESULTS: A total of 102 patients (76 ambulatory, 26 hospitalized) completed the symptom inventory and neurocognitive tests 24 ± 22 days following laboratory confirmation of SARS-CoV-2 infection. Hospitalized and ambulatory patients self-reported high rates of cognitive impairment (27-40%), without differences between the groups. However, hospitalized patients showed higher rates of objective impairment in visual memory (30% vs. 4%; p = 0.001) and psychomotor speed (41% vs. 15%; p = 0.008). Objective cognitive test performance was associated with anxiety, depression, fatigue, and pain in the ambulatory but not the hospitalized group. CONCLUSIONS: Focal cognitive deficits are more common in hospitalized than ambulatory patients. Cognitive performance is associated with neuropsychiatric symptoms in ambulatory but not hospitalized patients. Objective neurocognitive measures can provide essential information to inform neurologic triage and should be included as endpoints in clinical trials.

Cerebral toxoplasmosis in a patient with multiple myeloma.

Background: Cerebral toxoplasmosis is a rare complication of relapsed/refractory multiple myeloma (MM) after autologous stem cell transplant (SCT). Imaging characteristics can be helpful in leading to rapid diagnosis and treatment. Case Description: A 76-year-old man with relapsed/refractory IgA kappa MM status post autologous SCT who presented to the hospital with altered mental status. His hospital course was complicated by rapid decompensation to obtundation requiring intubation. Magnetic resonance imaging (MRI) of the brain revealed numerous ring-enhancing lesions with eccentric target signs, which were concerning for cerebral toxoplasmosis. Diagnosis was confirmed with positive toxoplasma cerebrospinal fluid polymerase chain reaction test. Conclusion: Cerebral toxoplasmosis should be considered in the differential diagnosis for MM patients who present with altered mental status and neurologic findings. The ring-enhancing lesion with eccentric target sign on MRI can be helpful in the diagnosis of cerebral toxoplasmosis.

Acute neurologic emerging flaviviruses.

The COVID-19 pandemic has shed light on the challenges we face as a global society in preventing and containing emerging and re-emerging pathogens. Multiple intersecting factors, including environmental changes, host immunological factors, and pathogen dynamics, are intimately connected to the emergence and re-emergence of communicable diseases. There is a large and expanding list of communicable diseases that can cause neurological damage, either through direct or indirect routes. Novel pathogens of neurotropic potential have been identified through advanced diagnostic techniques, including metagenomic next-generation sequencing, but there are also known pathogens which have expanded their geographic distribution to infect non-immune individuals. Factors including population growth, climate change, the increase in animal and human interface, and an increase in international travel and trade are contributing to the expansion of emerging and re-emerging pathogens. Challenges exist around antimicrobial misuse giving rise to antimicrobial-resistant infectious neurotropic organisms and increased susceptibility to infection related to the expanded use of immunomodulatory treatments. In this article, we will review key concepts around emerging and re-emerging pathogens and discuss factors associated with neurotropism and neuroinvasion. We highlight several neurotropic pathogens of interest, including West Nile virus (WNV), Zika Virus, Japanese Encephalitis Virus (JEV), and Tick-Borne Encephalitis Virus (TBEV). We emphasize neuroinfectious diseases which impact the central nervous system (CNS) and focus on flaviviruses, a group of vector-borne pathogens that have expanded globally in recent years and have proven capable of widespread outbreak.

Changes in the Epidemiology and Causative Pathogens of Meningitis in Children After the Outbreak of the Coronavirus Disease 2019: A Multicenter Database Study.

Background: With the outbreak of the COVID-19 pandemic, non-pharmaceutical interventions such as social distancing have been implemented worldwide, and a decrease in other infectious diseases has been reported as an unexpected benefit. However, to date, studies are lacking regarding the effects of the COVID-19 pandemic on neuroinfectious diseases; therefore, we aimed to determine the effects of the COVID-19 pandemic on the incidence of meningitis, which is the most common infectious disease in children. Methods: This retrospective study used electronic medical record data from five university hospitals located in the metropolitan cities in Korea. This study included patients aged <18 years who were diagnosed with meningitis between January 2017 and December 2020. We analyzed the clinical characteristics of patients with meningitis and changes in the incidence and causative pathogens of meningitis before and after the COVID-19 outbreak. Results: The study included 677 patients with meningitis. Following the outbreak of COVID-19 in Korea in January 2020, the incidence of childhood meningitis significantly decreased and seasonal changes noted yearly disappeared. There was a difference in the age distribution of patients with meningitis. The incidence of meningitis decreased significantly in children aged >5 years, and the incidence in children <5 years of age relatively increased (p < 0.001). In addition, there was a notable decrease in the cases of suspected meningitis (p < 0.001). The incidence of enteroviral meningitis, the most common cause of meningitis, significantly decreased. Conclusion: After the COVID-19 outbreak, the incidence of childhood meningitis significantly decreased with the implementation of non-pharmaceutical interventions. Absence of enteroviral meningitis and decrease in the proportion of patients aged ≥5 years with meningitis having mild symptoms were noted. Consequently, it can be concluded that the non-pharmaceutical interventions (NPIs) instituted to prevent the spread of COVID-19 had some effect on reducing the incidence of meningitis.

Clinical characteristics and outcomes after new-onset seizure among Zambian children with HIV during the antiretroviral therapy era.

OBJECTIVE: This study describes clinical profiles including human immunodeficiency virus (HIV) disease history and seizure etiology among children living with HIV presenting with new-onset seizure during the era of antiretroviral therapy (ART) in Zambia. 30-day mortality and cause of death are also reported. METHODS: Children living with HIV (CLWHIV) with new-onset seizures were prospectively evaluated at one large urban teaching hospital and two non-urban healthcare facilities. Interviews with family members, review of medical records, and where needed, verbal autopsies were undertaken. Two clinicians who were not responsible for the patients' care independently reviewed all records and assigned seizure etiology and cause of death with adjudication as needed. RESULTS: From April 2016 to June 2019, 73 children (49 urban, 24 rural) were identified. Median age was 6 years (IQR 2.2-10.0) and 39 (53%) were male children. Seizures were focal in 36 (49%) and were often severe, with 37% presenting with multiple recurrent seizures in the 24 hours before admission or in status epilepticus. Although 36 (49%) were on ART at enrollment, only 7 of 36 (19%) were virally suppressed. Seizure etiologies were infectious in over half (54%), with HIV encephalitis, bacterial meningitis, and tuberculous meningitis being the most common. Metabolic causes (19%) included renal failure and hypoglycemia. Structural lesions identified on imaging accounted for 10% of etiologies and included stroke and non-accidental trauma. No etiology could be identified in 12 (16%) children, most of whom died before the completion of clinical investigations. Twenty-two (30%) children died within 30 days of the index seizure. SIGNIFICANCE: Despite widespread ART roll out in Zambia, new-onset seizure in CLWHIV occurs in the setting of advanced, active HIV disease. Seizure severity/burden is high as is early mortality. Enhanced programs to assure early ART initiation, improve adherence, and address ART failure are needed to reduce the burden of neurological injury and premature death in CLWHIV.

Cryptogenic cervical intramedullary abscess with rapidly progressive myelopathy: illustrative case.

BACKGROUND: The purpose of the present case report is to highlight the presentation, workup, clinical decision making, and operative intervention for a 68-year-old woman who developed rapidly progressive myelopathy secondary to idiopathic cervical intramedullary abscess. OBSERVATIONS: The patient underwent laminectomy and aspiration/biopsy of the lesion. Intraoperatively, division of the posterior median sulcus released a large volume of purulent material growing the oral pathogens Eikenella corrodens and Gemella morbillorum. Broad-spectrum antibiotics were initiated postoperatively. At the 6-month follow-up, the patient had almost completely recovered with some persistent hand dysesthesia. Complete infectious workup, including full dental assessment and an echocardiogram, failed to reveal the source of her infection. LESSONS: The authors report the first case of cryptogenic spinal intramedullary abscess secondary to Eikenella spp. and Gemella spp. coinfection. Intramedullary abscesses are exceptionally rare and most commonly develop in children with dermal sinus malformations or in the context of immunosuppression. In adults without risk factors, they can readily be mistaken for more common pathologies in this age group, such as intramedullary neoplasms or demyelinating disease. Prompt diagnosis and management based on rapidly progressive myelopathy, assessment of infectious risk factors and/or symptoms, and targeted imaging are critical to avoid potentially devastating neurological sequelae.

Influenza B-associated encephalitis with rapid improvement with oseltamivir.

A 25-year-old female veterinarian presented with 1-week of flu-like symptoms followed by progressive encephalopathy. She was originally from Nicaragua and had been in the USA for 4 months. In the emergency department, she was confused and non-verbal with meningismus and facial myoclonus, but with an otherwise non-focal neurological exam. MRI brain abnormalities were consistent with viral encephalitides. Influenza B was detected via nasopharyngeal swab PCR. Mental status improved rapidly with oseltamivir. In such presentations, especially during flu season, influenza encephalitis must be considered, to facilitate early recognition of this entity and allow for targeted treatment.