Genomic analysis, immunomodulation and deep phenotyping of patients with nodding syndrome.

The aetiology of nodding syndrome remains unclear, and comprehensive genotyping and phenotyping data from patients remain sparse. Our objectives were to characterize the phenotype of patients with nodding syndrome, investigate potential contributors to disease aetiology, and evaluate response to immunotherapy. This cohort study investigated members of a single-family unit from Lamwo District, Uganda. The participants for this study were selected by the Ugandan Ministry of Health as representative for nodding syndrome and with a conducive family structure for genomic analyses. Of the eight family members who participated in the study at the National Institutes of Health (NIH) Clinical Center, three had nodding syndrome. The three affected patients were extensively evaluated with metagenomic sequencing for infectious pathogens, exome sequencing, spinal fluid immune analyses, neurometabolic and toxicology testing, continuous electroencephalography and neuroimaging. Five unaffected family members underwent a subset of testing for comparison. A distinctive interictal pattern of sleep-activated bursts of generalized and multifocal epileptiform discharges and slowing was observed in two patients. Brain imaging showed two patients had mild generalized cerebral atrophy, and both patients and unaffected family members had excessive metal deposition in the basal ganglia. Trace metal biochemical evaluation was normal. CSF was non-inflammatory and one patient had CSF-restricted oligoclonal bands. Onchocerca volvulus-specific antibodies were present in all patients and skin snips were negative for active onchocerciasis. Metagenomic sequencing of serum and CSF revealed hepatitis B virus in the serum of one patient. Vitamin B6 metabolites were borderline low in all family members and CSF pyridoxine metabolites were normal. Mitochondrial DNA testing was normal. Exome sequencing did not identify potentially causal candidate gene variants. Nodding syndrome is characterized by a distinctive pattern of sleep-activated epileptiform activity. The associated growth stunting may be due to hypothalamic dysfunction. Extensive testing years after disease onset did not clarify a causal aetiology. A trial of immunomodulation (plasmapheresis in two patients and intravenous immunoglobulin in one patient) was given without short-term effect, but longer-term follow-up was not possible to fully assess any benefit of this intervention.

The Brighton Collaboration case definition: Comparison in a retrospective and prospective cohort of children with Guillain-Barré syndrome.

Guillain-Barré syndrome (GBS) is an immune-mediated polyradiculoneuropathy frequently preceded by an infection with Campylobacter jejuni or nonspecific infections, and rarely by a vaccination. Due to a lack of a pathognomonic finding or biomarker, its diagnosis is based on a typical constellation of clinical and paraclinical symptoms and findings. The Brighton Collaboration GBS Working Group published in 2011 GBS case definitions and guidelines for diagnosis to improve the registration of GBS cases occurring in conjunction with vaccination programs worldwide. We applied these criteria to two historical studies on GBS in children and adolescents performed retrospectively from 1989 to 1994 and prospectively from 1998 to 2002. The clinical criteria were met in 91% of the retrospective and all of the prospective cases. CSF investigations were conducted in all patients and revealed cytoalbuminologic dissociation in 80% of the retrospective and 75% of the prospective cohort. Nerve conduction studies were performed in 61% and 69% of the cohorts, respectively, and were pathological in 92% each. The Brighton criteria are well suited to capture GBS in retro- and prospective studies. However, because they are designed to diagnose classical symmetric and ascending GBS and Fisher syndrome, very rare topographical variants of GBS such as the pharyngo-cervico-brachial variant and others could be missed.

Sudor Anglicus: an epidemic targeting the autonomic nervous system.

Renaissance England witnessed a series of brief epidemics of a rapid and often fatal illness, the predominant feature of which was a disturbance of the autonomic nervous system. Profuse sweating was both an emblematic and ominous sign of this Sudor Anglicus. Its story is medically fascinating as well as historically noteworthy. Possible sites of pathological involvement include the hypothalamus, serotonergic neurons in the brainstem or spinal cord, autonomic ganglia, peripheral sympathetic nerves, neuroeffector junctions, or eccrine glands. Of candidate etiologic agents, a virus is most likely, given the seasonal variation, geographic clustering, and pattern of spread of the epidemics. Hantaviruses, enteroviruses, influenza, and others provide clinical comparisons, but a definitive match with known viruses has remained elusive.

Guillain-Barré syndrome and antecedent cytomegalovirus infection, USA 2009-2015.

OBJECTIVE: To describe incidence and clinical characteristics of cases of Guillain-Barré syndrome (GBS) in the USA during 2009-2015, and characteristics of GBS cases with antecedent cytomegalovirus (CMV) infection among persons with employer-sponsored insurance. METHODS: We analyzed medical claims from IBM Watson MarketScan® databases. GBS patients were defined as enrollees with an inpatient claim with GBS as the principal diagnosis code, based on ICD-9 or ICD-10, and ≥ 1 claim for lumbar puncture or EMG/nerve conduction study. We assessed intensive care unit (ICU) hospitalization, intubation, dysautonomia, and death. We also assessed selected infectious illness within 60 days prior to the first GBS-coded inpatient claim. RESULTS: We identified 3486 GBS patients; annual incidence was 1.0-1.2/100,000 persons during 2009-2015. GBS incidence was higher in males (1.2/100,000) than in females (0.9/100,000) (p = 0.006) and increased with age, from 0.4/100,000 in persons 0-17 years old to 2.1/100,000 in persons ≥ 65 years old (p < 0.001). Half of GBS patients were hospitalized in the ICU, 8% were intubated, 2% developed dysautonomia, and 1% died. Half had a claim for antecedent illness, but only 125 (3.5%) had a claim for specific infectious pathogens. The mean age among 18 GBS patients with antecedent CMV infection was 39 years versus 47 years among those without antecedent  CMV infection (p = 0.038). CONCLUSIONS: Incidence of GBS using a large national claims database was comparable to that reported in the literature, but cases appeared to be less severe. Half of GBS patients reported prior infectious illness, but only a minority had a specific pathogen identified.

Guillain-Barré syndrome risk among individuals infected with Zika virus: a multi-country assessment.

BACKGROUND: Countries with ongoing outbreaks of Zika virus have observed a notable rise in reported cases of Guillain-Barré syndrome (GBS), with mounting evidence of a causal link between Zika virus infection and the neurological syndrome. However, the risk of GBS following a Zika virus infection is not well characterized. In this work, we used data from 11 locations with publicly available data to estimate the risk of GBS following an infection with Zika virus, as well as the location-specific incidence of infection and the number of suspect GBS cases reported per infection. METHODS: We built a mathematical inference framework utilizing data from 11 locations that had reported suspect Zika and GBS cases, two with completed outbreaks prior to 2015 (French Polynesia and Yap) and nine others in the Americas covering partial outbreaks and where transmission was ongoing as of early 2017. RESULTS: We estimated that 2.0 (95% credible interval 0.5-4.5) reported GBS cases may occur per 10,000 Zika virus infections. The frequency of reported suspect Zika cases varied substantially and was highly uncertain, with a mean of 0.11 (95% credible interval 0.01-0.24) suspect cases reported per infection. CONCLUSIONS: These estimates can help efforts to prepare for the GBS cases that may occur during Zika epidemics and highlight the need to better understand the relationship between infection and the reported incidence of clinical disease.

Zika Virus -10 Public Health Achievements in 2016 and Future Priorities.

The introduction of Zika virus into the Region of the Americas (Americas) and the subsequent increase in cases of congenital microcephaly resulted in activation of CDC's Emergency Operations Center on January 22, 2016, to ensure a coordinated response and timely dissemination of information, and led the World Health Organization to declare a Public Health Emergency of International Concern on February 1, 2016. During the past year, public health agencies and researchers worldwide have collaborated to protect pregnant women, inform clinicians and the public, and advance knowledge about Zika virus (Figure 1). This report summarizes 10 important contributions toward addressing the threat posed by Zika virus in 2016. To protect pregnant women and their fetuses and infants from the effects of Zika virus infection during pregnancy, public health activities must focus on preventing mosquito-borne transmission through vector control and personal protective practices, preventing sexual transmission by advising abstention from sex or consistent and correct use of condoms, and preventing unintended pregnancies by reducing barriers to access to highly effective reversible contraception.

Acute Flaccid Myelitis in the United States, August-December 2014: Results of Nationwide Surveillance.

BACKGROUND: During late summer/fall 2014, pediatric cases of acute flaccid myelitis (AFM) occurred in the United States, coincident with a national outbreak of enterovirus D68 (EV-D68)-associated severe respiratory illness. METHODS: Clinicians and health departments reported standardized clinical, epidemiologic, and radiologic information on AFM cases to the Centers for Disease Control and Prevention (CDC), and submitted biological samples for testing. Cases were ≤21 years old, with acute onset of limb weakness 1 August-31 December 2014 and spinal magnetic resonance imaging (MRI) showing lesions predominantly restricted to gray matter. RESULTS: From August through December 2014, 120 AFM cases were reported from 34 states. Median age was 7.1 years (interquartile range, 4.8-12.1 years); 59% were male. Most experienced respiratory (81%) or febrile (64%) illness before limb weakness onset. MRI abnormalities were predominantly in the cervical spinal cord (103/118). All but 1 case was hospitalized; none died. Cerebrospinal fluid (CSF) pleocytosis (>5 white blood cells/µL) was common (81%). At CDC, 1 CSF specimen was positive for EV-D68 and Epstein-Barr virus by real-time polymerase chain reaction, although the specimen had >3000 red blood cells/µL. The most common virus detected in upper respiratory tract specimens was EV-D68 (from 20%, and 47% with specimen collected ≤7 days from respiratory illness/fever onset). Continued surveillance in 2015 identified 16 AFM cases reported from 13 states. CONCLUSIONS: Epidemiologic data suggest this AFM cluster was likely associated with the large outbreak of EV-D68-associated respiratory illness, although direct laboratory evidence linking AFM with EV-D68 remains inconclusive. Continued surveillance will help define the incidence, epidemiology, and etiology of AFM.

Enterovirus D68 Infection in Children with Acute Flaccid Myelitis, Colorado, USA, 2014.

During August 8, 2014-October 14, 2014, a total of 11 children with acute flaccid myelitis and distinctive neuroimaging changes were identified near Denver, Colorado, USA. A respiratory prodrome was experienced by 10, and nasopharyngeal specimens were positive for enterovirus D68 (EV-D68) for 4. To determine whether an association exists between EV-D68 infection and acute flaccid myelitis, we conducted a retrospective case-control study comparing these patients with 2 groups of outpatient control children (1 group tested for acute respiratory illness and 1 for Bordetella pertussis infection). Adjusted analyses indicated that, for children with acute flaccid myelitis, the odds of having EV-D68 infection were 10.3 times greater than for those tested for acute respiratory infection and 4.5 times greater than for those tested for B. pertussis infection. No statistical association was seen between acute flaccid myelitis and non-EV-D68 enterovirus or rhinovirus infection. These findings support an association between EV-D68 infection and acute flaccid myelitis.

Outbreak of henipavirus infection, Philippines, 2014.

During 2014, henipavirus infection caused severe illness among humans and horses in southern Philippines; fatality rates among humans were high. Horse-to-human and human-to-human transmission occurred. The most likely source of horse infection was fruit bats. Ongoing surveillance is needed for rapid diagnosis, risk factor investigation, control measure implementation, and further virus characterization.

Outbreaks of unexplained neurologic illness - Muzaffarpur, India, 2013-2014.

Outbreaks of an unexplained acute neurologic illness affecting young children and associated with high case-fatality rates have been reported in the Muzaffarpur district of Bihar state in India since 1995. The outbreaks generally peak in June and decline weeks later with the onset of monsoon rains. There have been multiple epidemiologic and laboratory investigations of this syndrome, leading to a wide spectrum of proposed causes for the illness, including infectious encephalitis and exposure to pesticides. An association between illness and litchi fruit has been postulated because Muzaffarpur is a litchi fruit-producing region. To better characterize clinical and epidemiologic features of the illness that might suggest its cause and how it can be prevented, the Indian National Centre for Disease Control (NCDC) and CDC investigated outbreaks in 2013 and 2014. Clinical and laboratory findings in 2013 suggested a noninflammatory encephalopathy, possibly caused by a toxin. A common laboratory finding was low blood glucose (<70 mg/dL) on admission, a finding associated with a poorer outcome; 44% of all cases were fatal. An ongoing 2014 investigation has found no evidence of any infectious etiology and supports the possibility that exposure to a toxin might be the cause. The outbreak period coincides with the month-long litchi harvesting season in Muzaffarpur. Although a specific etiology has not yet been determined, the 2014 investigation has identified the illness as a hypoglycemic encephalopathy and confirmed the importance of ongoing laboratory evaluation of environmental toxins to identify a potential causative agent, including markers for methylenecyclopropylglycine (MCPG), a compound found in litchi seeds known to cause hypoglycemia in animal studies. Current public health recommendations are focused on reducing mortality by urging affected families to seek prompt medical care, and ensuring rapid assessment and correction of hypoglycemia in ill children.

Encephalitis caused by pathogens transmitted through organ transplants, United States, 2002-2013.

The cause of encephalitis among solid organ transplant recipients may be multifactorial; the disease can result from infectious or noninfectious etiologies. During 2002-2013, the US Centers for Disease Control and Prevention investigated several encephalitis clusters among transplant recipients. Cases were caused by infections from transplant-transmitted pathogens: West Nile virus, rabies virus, lymphocytic choriomeningitis virus, and Balamuthia mandrillaris amebae. In many of the clusters, identification of the cause was complicated by delayed diagnosis due to the rarity of the disease, geographic distance separating transplant recipients, and lack of prompt recognition and reporting systems. Establishment of surveillance systems to detect illness among organ recipients, including communication among transplant center physicians, organ procurement organizations, and public health authorities, may enable the rapid discovery and investigation of infectious encephalitis clusters. These transplant-transmitted pathogen clusters highlight the need for greater awareness among clinicians, pathologists, and public health workers, of emerging infectious agents causing encephalitis among organ recipients.

Trends in encephalitis-associated deaths in the United States, 1999-2008.

BACKGROUND: While encephalitis may be caused by numerous infectious, immune and toxic processes, the etiology often remains unknown. METHODS: We analyzed multiple cause-of-death mortality data during 1999-2008 for the USA, using the 10th revision of International Classification of Diseases codes for encephalitis, listed anywhere on the death record, including 'specified' and 'unspecified' encephalitis. Annual and average annual age-adjusted and age-specific death rates were calculated. RESULTS: For 1999-2008, 12,526 encephalitis-associated deaths were reported with 68.5% as unspecified encephalitis. The average annual age-adjusted encephalitis-associated death rate was 4.3 per 1 million persons, 1.3 for specified and 2.9 for unspecified encephalitis. Annual encephalitis-associated death rates had a significant downward trend (p < 0.01). The most common specified encephalitis deaths were herpesviral encephalitis (36.7%), Toxoplasma meningoencephalitis (27.8%) and Listeria meningitis/meningoencephaltis (6.8%). HIV was colisted with 15.0% of encephalitis-associated deaths, 58.4% of these with a specified code. CONCLUSION: Encephalitis-associated death rates decreased during 1999-2008, and herpesvirus was the most commonly identified infectious agent associated with encephalitis deaths. The high proportion of unspecified encephalitis deaths highlights the continued challenge of laboratory confirmation for causes of encephalitis and the importance of monitoring trends to assess the impact of new diagnostics and guide potential interventions.

Clinical, laboratory, diagnostic, and histopathologic features of diethylene glycol poisoning--Panama, 2006.

STUDY OBJECTIVE: Diethylene glycol is a toxic industrial solvent responsible for more than 13 mass poisonings since 1937. Little is known about the clinical spectrum, progression, and neurotoxic potential of diethylene glycol-associated disease because of its high mortality and the absence of detailed information in published mass poisoning reports. This incident includes the largest proportion of cases with neurotoxic signs and symptoms. We characterize the features of a diethylene glycol mass poisoning resulting from a contaminated cough syrup distributed in Panama during 2006. METHODS: This was a retrospective chart review and descriptive analysis in a tertiary level, urban health care facility. A case was a person admitted to the Social Security Metropolitan Hospital in Panama City between June 1 and October 22, 2006, with unexplained acute kidney injury and a serum creatinine level of greater than or equal to 2 mg/dL, or unexplained chronic renal failure exacerbation (>2-fold increase in baseline serum creatinine level) and history of implicated cough syrup exposure. Main outcomes and measures were demographic, clinical, laboratory, diagnostic, histopathologic, and mortality data with descriptive statistics. RESULTS: Forty-six patients met inclusion criteria. Twenty-four (52%) were female patients; median age was 67 years (range 25 to 91 years). Patients were admitted with acute kidney injury or a chronic renal failure exacerbation (median serum creatinine level 10.0 mg/dL) a median of 5 days after symptom onset. Forty patients (87%; 95% confidence interval [CI] 74% to 95%) had neurologic signs, including limb (n=31; 77%; 95% CI 62% to 89%) or facial motor weakness (n=27; 68%; 95% CI 51% to 81%). Electrodiagnostics in 21 patients with objective weakness demonstrated a severe sensorimotor peripheral neuropathy (n=19; 90%; 95% CI 70% to 99%). In 14 patients without initial neurologic findings, elevated cerebrospinal fluid protein concentrations without pleocytosis were observed: almost all developed overt neurologic illness (n=13; 93%; 95% CI 66% to 100%). Despite use of intensive care and hemodialysis therapies, 27 (59%) died a median of 19 days (range 2 to 50 days) after presentation. CONCLUSION: A high proportion of patients with diethylene glycol poisoning developed progressive neurologic signs and symptoms in addition to acute kidney injury. Facial or limb weakness with unexplained acute kidney injury should prompt clinicians to consider diethylene glycol poisoning. Elevated cerebrospinal fluid protein concentrations without pleocytosis among diethylene glycol-exposed persons with acute kidney injury may be a predictor for progressive neurologic illness.

Clinical features, etiologies, and outcomes of central nervous system infections in intensive care: A multicentric retrospective study in a large Brazilian metropolitan area.

PURPOSE: The goal of this study was to investigate severe central nervous system infections (CNSI) in adults admitted to the intensive care unit (ICU). We analyzed the clinical presentation, causes, and outcomes of these infections, while also identifying factors linked to higher in-hospital mortality rates. MATERIALS AND METHODS: We conducted a retrospective multicenter study in Rio de Janeiro, Brazil, from 2012 to 2019. Using a prediction tool, we selected ICU patients suspected of having CNSI and reviewed their medical records. Multivariate analyses identified variables associated with in-hospital mortality. RESULTS: In a cohort of 451 CNSI patients, 69 (15.3%) died after a median 11-day hospitalization (5-25 IQR). The distribution of cases was as follows: 29 (6.4%) had brain abscess, 161 (35.7%) had encephalitis, and 261 (57.8%) had meningitis. Characteristics: median age 41 years (27-53 IQR), 260 (58%) male, and 77 (17%) HIV positive. The independent mortality predictors for encephalitis were AIDS (OR = 4.3, p = 0.01), ECOG functional capacity limitation (OR = 4.0, p < 0.01), ICU admission from ward (OR = 4.0, p < 0.01), mechanical ventilation ≥10 days (OR = 6.1, p = 0.04), SAPS 3 ≥ 55 points (OR = 3.2, p = 0.02). Meningitis: Age > 60 years (OR = 234.2, p = 0.04), delay >3 days for treatment (OR = 2.9, p = 0.04), mechanical ventilation ≥10 days (OR = 254.3, p = 0.04), SOFA >3 points (OR = 2.7, p = 0.03). Brain abscess: No associated factors found in multivariate regression. CONCLUSIONS: Patients' overall health, prompt treatment, infection severity, and prolonged respiratory support in the ICU all significantly affect in-hospital mortality rates. Additionally, the implementation of CNSI surveillance with the used prediction tool could enhance public health policies.

Nodding syndrome.

An epidemic illness characterized by head nodding associated with onchocerciasis has been described in eastern Africa since the early 1960s; we summarize published reports and recent studies. Onset of nodding occurs in previously healthy 5-15-year-old children and is often triggered by eating or cold temperatures and accompanied by cognitive impairment. Its incidence has increased in Uganda and South Sudan over the past 10 years. Four case-control studies identified modest and inconsistent associations. There were nonspecific lesions seen by magnetic resonance imaging, no cerebrospinal fluid inflammation, and markedly abnormal electroencephalography results. Nodding episodes are atonic seizures. Testing has failed to demonstrate associations with trypanosomiasis, cysticercosis, loiasis, lymphatic filariasis, cerebral malaria, measles, prion disease, or novel pathogens; or deficiencies of folate, cobalamin, pyridoxine, retinol, or zinc; or toxicity from mercury, copper, or homocysteine. There is a consistent enigmatic association with onchocerciasis detected by skin snip or serologic analysis. Nodding syndrome is an unexplained epidemic epilepsy.

Guillain-Barre syndrome during the 2009-2010 H1N1 influenza vaccination campaign: population-based surveillance among 45 million Americans.

Because of widespread distribution of the influenza A (H1N1) 2009 monovalent vaccine (pH1N1 vaccine) and the prior association between Guillain-Barré syndrome (GBS) and the 1976 H1N1 influenza vaccine, enhanced surveillance was implemented to estimate the magnitude of any increased GBS risk following administration of pH1N1 vaccine. The authors conducted active, population-based surveillance for incident cases of GBS among 45 million persons residing at 10 Emerging Infections Program sites during October 2009-May 2010; GBS was defined according to published criteria. The authors determined medical and vaccine history for GBS cases through medical record review and patient interviews. The authors used vaccine coverage data to estimate person-time exposed and unexposed to pH1N1 vaccine and calculated age- and sex-adjusted rate ratios comparing GBS incidence in these groups, as well as age- and sex-adjusted numbers of excess GBS cases. The authors received 411 reports of confirmed or probable GBS. The rate of GBS immediately following pH1N1 vaccination was 57% higher than in person-time unexposed to vaccine (adjusted rate ratio = 1.57, 95% confidence interval: 1.02, 2.21), corresponding to 0.74 excess GBS cases per million pH1N1 vaccine doses (95% confidence interval: 0.04, 1.56). This excess risk was much smaller than that observed during the 1976 vaccine campaign and was comparable to some previous seasonal influenza vaccine risk assessments.

West nile virus RNA not detected in urine of 40 people tested 6 years after acute West Nile virus disease.

West Nile virus (WNV) causes an acute infection that is usually cleared by an effective immune response after several days of viremia. However, a recent study detected WNV RNA in the urine of 5 of 25 persons (20%) tested several years after their initial acute WNV disease. We evaluated an established cohort of 40 persons >6 years after initial infection with WNV. Urine collected from all participants tested negative for WNV RNA by reverse-transcription polymerase chain reaction and transcription-mediated amplification. Prospective studies are needed to determine if and for how long WNV persists in urine following WNV disease.

Duration of West Nile Virus Immunoglobulin M Antibodies up to 81 Months Following West Nile Virus Disease Onset.

West Nile virus (WNV) IgM antibodies typically indicate a recent infection. However, WNV IgM antibodies can remain detectable for months to years following illness onset. We found that 23% (11/47) of samples tested with a WNV ELISA and 43% (20/47) of samples tested with WNV microsphere immunoassay (MIA) at 16-19 months following WNV illness onset were positive for IgM antibodies. The proportion of samples testing positive for WNV IgM by ELISA decreased over time, but 5% (2/44) of individuals remained positive at 60-63 months after their acute illness and 4% (2/50) were WNV IgM equivocal at 72-81 months. Testing by MIA showed the same general trend of decreased proportion positive over time though the rates of positivity were higher at most time points compared with the ELISA, including 6% (3/50) of participant's samples identified as IgM positive by MIA at 72-81 months post their acute illness. With the MIA, there also was a high proportion of samples with nonspecific results at each time point; average of 23% across all time points. Clinicians and public health officials should consider these findings along with clinical and epidemiologic data when interpreting WNV IgM antibody test results.

Population-based assessment of risks for severe COVID-19 disease outcomes.

Among approximately 4.6 million members of Kaiser Permanente Northern California, we examined associations of severe COVID-19 with demographic factors and comorbidities. As of July 23, 2021, 16 182 had been hospitalized, 2416 admitted to an ICU, and 1525 died due to COVID-19. Age was strongly associated with hospitalization, ICU admission, and death. Black persons and Hispanic ethnicity had higher risk of death compared with Whites. Among the comorbidities examined, Alzheimer's disease was associated with the highest risk for hospitalization (aHR 3.19, CI: 2.88-3.52) and death (aHR 4.04, CI: 3.32-4.91). Parkinson's disease had the second highest risk of death (aHR = 2.07, CI: 1.50-2.87).