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Fulltext The Use of Large-Particle Aerosol Exposure to Nipah Virus to Mimic Human Neurological Disease Manifestations in the African Green Monkey

Lee JH, Hammoud DA, Cong Y, Huzella LM, Castro MA, Solomon J, et al.

J Infect Dis, 2020 05 11;221(Suppl 4):S419-S430.
PMID: 31687756 DOI: 10.1093/infdis/jiz502

Nipah virus (NiV) is an emerging virus associated with outbreaks of acute respiratory disease and encephalitis. To develop a neurological model for NiV infection, we exposed 6 adult African green monkeys to a large-particle (approximately 12 μm) aerosol containing NiV (Malaysian isolate). Brain magnetic resonance images were obtained at baseline, every 3 days after exposure for 2 weeks, and then weekly until week 8 after exposure. Four of six animals showed abnormalities reminiscent of human disease in brain magnetic resonance images. Abnormalities ranged from cytotoxic edema to vasogenic edema. The majority of lesions were small infarcts, and a few showed inflammatory or encephalitic changes. Resolution or decreased size in some lesions resembled findings reported in patients with NiV infection. Histological lesions in the brain included multifocal areas of encephalomalacia, corresponding to known ischemic foci. In other regions of the brain there was evidence of vasculitis, with perivascular infiltrates of inflammatory cells and rare intravascular fibrin thrombi. This animal model will help us better understand the acute neurological features of NiV infection and develop therapeutic approaches for managing disease caused by NiV infection.

Matched MeSH terms: Central Nervous System Infections/pathology; Central Nervous System Infections/virology*
Fulltext Brain-Eating Amoebae: Predilection Sites in the Brain and Disease Outcome

Ong TYY, Khan NA, Siddiqui R

J Clin Microbiol, 2017 07;55(7):1989-1997.
PMID: 28404683 DOI: 10.1128/JCM.02300-16

Acanthamoeba spp. and Balamuthia mandrillaris are causative agents of granulomatous amoebic encephalitis (GAE), while Naegleria fowleri causes primary amoebic meningoencephalitis (PAM). PAM is an acute infection that lasts a few days, while GAE is a chronic to subacute infection that can last up to several months. Here, we present a literature review of 86 case reports from 1968 to 2016, in order to explore the affinity of these amoebae for particular sites of the brain, diagnostic modalities, treatment options, and disease outcomes in a comparative manner.

Matched MeSH terms: Central Nervous System Infections/parasitology*; Central Nervous System Infections/pathology*
Blood brain barrier and infection

Chaudhuri JD

Med Sci Monit, 2000 Nov-Dec;6(6):1213-22.
PMID: 11208482

The blood brain barrier (BBB) is a highly dynamic structure and consists of endothelial cells, which are characterized by the presence of tight junctions and relative lack of endocytic vesicles. The tight junctions are reinforced by the foot processes of the astrocytes. The BBB functions through these specialised structures, to maintain the environment of the brain in a steady state by regulating the influx and efflux of substances. The protective effect of the BBB is however, lost during bacterial and viral infections. The primary mechanism operative are an increase in the permeability of the BBB and/or direct invasion of the brain by microorganisms. Since the BBB is relatively impermeable to chemotherapeutic agents the treatment of CNS infections is difficult. This paper aims to examine the various mechanisms by which infection spreads to the brain, and suggest measures for successful drug delivery into the brain during infections.

Matched MeSH terms: Central Nervous System Infections/drug therapy; Central Nervous System Infections/physiopathology*
Fulltext An unusual case of primary melioidotic prostatic abscess complicated by perianal abscess

Chee YC, Chee YN

IDCases, 2018;11:51-52.
PMID: 29349040 DOI: 10.1016/j.idcr.2018.01.001

Burkholderia pseudomallei is recognized to cause severe and fatal infections. Most of the infections caused by this facultative intracellular gram-negative bacterium are pneumonia, soft tissue, genito-urinary and central nervous system infection. We report an unusual case of primary prostatic abscess complicated by perianal abscess caused by Burkholderia pseudomallei. Melioidosis related anorectal infections have not been previously reported in the literature.

Matched MeSH terms: Central Nervous System Infections
Coxsackievirus A16 in a 1-Day-Old Mouse Model of Central Nervous System Infection Shows Lower Neurovirulence than Enterovirus A71

Hooi YT, Ong KC, Tan SH, Perera D, Wong KT

J Comp Pathol, 2020 Apr;176:19-32.
PMID: 32359633 DOI: 10.1016/j.jcpa.2020.02.001

Coxsackievirus A16 (CV-A16) and enterovirus A71 (EV-A71) are the major causes of hand, foot and mouth disease in young children. Although less so with CV-A16, both viruses are associated with serious neurological syndromes, but the differences between their central nervous system infections remain unclear. We conducted a comparative infection study using clinically-isolated CV-A16 and EV-A71 strains in a 1-day-old mouse model to better understand the neuropathology and neurovirulence of the viruses. New serotype-specific probes for in situ hybridization were developed and validated to detect CV-A16 and EV-A71 RNA in infected tissues. Demonstration of CV-A16 virus antigens/RNA, mainly in the brainstem and spinal cord neurons, confirmed neurovirulence, but showed lower densities than in EV-A71 infected animals. A higher lethal dose50 for CV-A16 suggested that CV-A16 is less neurovirulent. Focal virus antigens/RNA in the anterior horn white matter and adjacent efferent motor nerves suggested that neuroinvasion is possibly via retrograde axonal transport in peripheral motor nerves.

Matched MeSH terms: Central Nervous System Infections/virology*
Epilepsy in the tropics: Emerging etiologies

Carrizosa Moog J, Kakooza-Mwesige A, Tan CT

Seizure, 2017 Jan;44:108-112.
PMID: 27986419 DOI: 10.1016/j.seizure.2016.11.032

Epilepsy is considered by the World Health Organization a public health priority with more than 50 million human beings affected by the disease. More than 80% of persons with epilepsy live in low and middle income countries and most of them in tropical areas. Several emerging, re-emerging and neglected diseases are symptomatic etiologies that jointly contribute to the enormous global burden of epilepsy. Besides the clinical strengths to reduce diagnostic and treatment gaps, other strategies in social, economic, cultural, educational and health policies are needed to prevent and treat appropriately vulnerable and affected persons with epilepsy. From the public health point of view, several of those strategies could be more effective in reducing the incidence and burden of the disease than the clinical approach of diagnosis and treatment. Special attention has to be given to stigma reduction and promotion of human rights. Several aspects mentioned in this abstract slip away the scope of the article, but it is a remainder to approach epilepsy in an inter- and transdisciplinary manner, an integral and pertinent approach needed and requested in tropical counties. The article focuses only on emergent and re-emergent etiologies of epilepsy in the tropics like malaria, HIV, neurocysticercosis, viral encephalitis and traumatic brain injury.

Matched MeSH terms: Central Nervous System Infections/complications*
Fulltext Tuberculous meningitis is a major cause of mortality and morbidity in adults with central nervous system infections in Kota Kinabalu, Sabah, Malaysia: an observational study

Lee HG, William T, Menon J, Ralph AP, Ooi EE, Hou Y, et al.

BMC Infect Dis, 2016 06 16;16:296.
PMID: 27306100 DOI: 10.1186/s12879-016-1640-x

BACKGROUND: Central nervous system (CNS) infections are a significant contributor to morbidity and mortality globally. However, most published studies have been conducted in developed countries where the epidemiology and aetiology differ significantly from less developed areas. Additionally, there may be regional differences due to variation in the socio-economic levels, public health services and vaccination policies. Currently, no prospective studies have been conducted in Sabah, East Malaysia to define the epidemiology and aetiology of CNS infections. A better understanding of these is essential for the development of local guidelines for diagnosis and management.
METHODS: We conducted a prospective observational cohort study in patients aged 12 years and older with suspected central nervous system infections at Queen Elizabeth Hospital, Kota Kinabalu, Sabah, Malaysia between February 2012 and March 2013. Cerebrospinal fluid was sent for microscopy, biochemistry, bacterial and mycobacterial cultures, Mycobacterium tuberculosis polymerase chain reaction (PCR), and multiplex and MassCode PCR for various viral and bacterial pathogens.
RESULTS: A total of 84 patients with clinically suspected meningitis and encephalitis were enrolled. An aetiological agent was confirmed in 37/84 (44 %) of the patients. The most common diagnoses were tuberculous meningitis (TBM) (41/84, 48.8 %) and cryptococcal meningoencephalitis (14/84, 16.6 %). Mycobacterium tuberculosis was confirmed in 13/41 (31.7 %) clinically diagnosed TBM patients by cerebrospinal fluid PCR or culture. The acute case fatality rate during hospital admission was 16/84 (19 %) in all patients, 4/43 (9 %) in non-TBM, and 12/41 (29 %) in TBM patients respectively (p = 0.02).
CONCLUSION: TBM is the most common cause of CNS infection in patients aged 12 years or older in Kota Kinabalu, Sabah, Malaysia and is associated with high mortality and morbidity. Further studies are required to improve the management and outcome of TBM.

Matched MeSH terms: Central Nervous System Infections/cerebrospinal fluid; Central Nervous System Infections/microbiology; Central Nervous System Infections/mortality; Central Nervous System Infections/epidemiology
Fulltext Multi-assay investigation of viral etiology in pediatric central nervous system infections

Altay-Kocak A, Bozdayi G, Michel J, Polat M, Kanik-Yuksek S, Tezer H, et al.

J Infect Dev Ctries, 2020 06 30;14(6):572-579.
PMID: 32683347 DOI: 10.3855/jidc.12327

INTRODUCTION: In an attempt to identify a wide spectrum of viral infections, cerebrospinal fluid (CSF) specimens were collected from pediatric cases with the preliminary diagnosis of viral encephalitis/meningoencephalitis in two reference hospitals, from October 2011 to December 2015.
METHODOLOGY: A combination of nucleic acid-based assays, including in house generic polymerase chain reaction (PCR) assays for enteroviruses, flaviviruses and phleboviruses, a commercial real-time PCR assay for herpesviruses and a commercial real time multiplex PCR, enabling detection of frequently-observed viral, bacterial and fungal agents were employed for screening.
RESULTS: The microbial agent could be characterized in 10 (10%) of the 100 specimens. Viral etiology could be demonstrated in 7 (70%) specimens, which comprises Human Herpesvirus 6 (4/7), Herpes Simplex virus type1 (2/7) and Enteroviruses (1/7). In 3 specimens (30%), Streptococcus pneumoniae, Listeria monocytogenes and Staphylococcus aureus were detected via the multiplex PCR, which were also isolated in bacteriological media. All specimens with detectable viral nucleic acids, as well as unreactive specimens via nucleic acid testing remained negative in bacteriological cultures.
CONCLUSIONS: Herpes and enteroviruses were identified as the primary causative agents of central nervous system infections in children. Enterovirus testing must be included in the diagnostic work-up of relevant cases.

Matched MeSH terms: Central Nervous System Infections/cerebrospinal fluid; Central Nervous System Infections/diagnosis; Central Nervous System Infections/etiology*; Central Nervous System Infections/virology*
Japanese Encephalitis Virus Infects the Thalamus Early Followed by Sensory-Associated Cortex and Other Parts of the Central and Peripheral Nervous Systems

Fu TL, Ong KC, Tan SH, Wong KT

J. Neuropathol. Exp. Neurol., 2019 12 01;78(12):1160-1170.
PMID: 31675093 DOI: 10.1093/jnen/nlz103

Japanese encephalitis (JE) is a known CNS viral infection that often involves the thalamus early. To investigate the possible role of sensory peripheral nervous system (PNS) in early neuroinvasion, we developed a left hindlimb footpad-inoculation mouse model to recapitulate human infection by a mosquito bite. A 1-5 days postinfection (dpi) study, demonstrated focal viral antigens/RNA in contralateral thalamic neurons at 3 dpi in 50% of the animals. From 4 to 5 dpi, gradual increase in viral antigens/RNA was observed in bilateral thalami, somatosensory, and piriform cortices, and then the entire CNS. Infection of neuronal bodies and adjacent nerves in dorsal root ganglia (DRGs), trigeminal ganglia, and autonomic ganglia (intestine, etc.) was also observed from 5 dpi. Infection of explant organotypic whole brain slice cultures demonstrated no viral predilection for the thalamus, while DRG and intestinal ganglia organotypic cultures confirmed sensory and autonomic ganglia susceptibility to infection, respectively. Early thalamus and sensory-associated cortex involvement suggest an important role for sensory pathways in neuroinvasion. Our results suggest that JE virus neuronotropism is much more extensive than previously known, and that the sensory PNS and autonomic system are susceptible to infection.

Matched MeSH terms: Central Nervous System Infections/pathology; Central Nervous System Infections/virology
Consent for lumbar puncture -factors that influence the decision

Malik, A.S.

Malaysian Journal of Paediatrics and Child Health, 2000;12(1):35-41.
MyJurnal

Lumbar puncture (LP) is an important procedure both for diagnostic and therapeutic purposes. In Kelantan, Malaysia, on many occasions consent for this procedure is not granted by patients or guardians. The aim of this study was to find out the factors that influence the decision to grant or refuse the consent for LP. This was a cross-sectional study in which 86 parents (who agreed or refused to give consent for LP on their child) were interviewed by using a standard questionnaire. A scoring system was used to assess their knowledge about the purpose and technique of the procedure. Consent for LP was granted in 23 and refused in 27 children. The refusal rate was significantly higher when family members other than parents made the decision. The factors which did not play a statistically significant role in decision-making included: age of the child and parents; gender of the patient; number of children in the family; patient's birth order among the siblings; place of residence; monthly income of the family; parents' level of education; and number of days after admission when LP was requested. The factors that positively influenced the decision to give consent included knowledge about the purpose of LP and underlying disease. In order to receive positive consent for LP it is concluded that the parents/guardians and other family members who may influence the decision-making should be explained the role of LP in (1) making diagnosis and (2) choosing right antibiotics for treatment. They should also be informed about the side-effects of antibiotics, which may be used unnecessarily in unconfirmed cases of central nervous system infections.

Matched MeSH terms: Central Nervous System Infections
Focal non-typhoidal Salmonella infections from a single center in Malaysia

Lee WS, Hafeez A, Hassan H, Raja NS, Puthucheary SD

Southeast Asian J Trop Med Public Health, 2005 May;36(3):678-82.
PMID: 16124437

A retrospective review of patients with focal non-typhoidal Salmonella (NTS) infection was performed to determine its features and outcome. All patients with focal NTS infection admitted to the University of Malaya Medical Center, Malaysia, from 1993 to 2002 were studied. More than half (58%) of the 35 cases (54% male, median age 39 years, range 1.5 months to 79 years) were immunocompromized or had chronic medical conditions. One-third of the patients (34%) had superficial infections (lymphadenitis or subcutaneous tissue infection) and all recovered with antimicrobial therapy alone. Deep infections (66%) noted were: meningitis (9%), osteomyelitis or arthritis (26%), abscesses of the gastrointestinal tract or adjacent organs (20%), and others (11%). Deep infections were more likely to occur in the extremes of age (<6 months or >60 years, p< 0.04), associated with adverse outcomes with an overall mortality rate of 9%, or required major surgery (15%).

Matched MeSH terms: Central Nervous System Infections/microbiology
Fulltext Melioidosis in acute cholangitis of diabetic patient: a forgotten diagnosis

Mohamad N, Ponnusamy S, Devi S, Manikam R, Idrus II, Bakar NHA

Res Rep Trop Med, 2012;3:103-106.
PMID: 30100777 DOI: 10.2147/RRTM.S34483

Melioidosis presents with a wide range of clinical presentations, which include severe community-acquired pneumonia, septicemia, central nervous system infection, and less severe soft tissue infection. Hence, its diagnosis depends heavily on the clinical microbiology laboratory for culture. In this case report, we describe an atypical presentation of melioidosis in a 52-year-old man who had fever, right upper-abdominal pain, and jaundice for 15 days. Melioidosis caused by Burkholderia pseudomallei was subsequently diagnosed from blood culture. As a primary care physician, high suspicion index is of great importance. High suspicion index of melioidosis in a high-risk group patient, such as the patient with diabetes mellitus and diabetic foot, is crucial in view of atypical presentations of pseudomonas sepsis. A correct combination of antibiotic administration in the early phase of therapy will determine its successful outcome.

Matched MeSH terms: Central Nervous System Infections
Fulltext Modelling person-to-person transmission in an Enterovirus A71 orally infected hamster model of hand-foot-and-mouth disease and encephalomyelitis

Phyu WK, Ong KC, Wong KT

Emerg Microbes Infect, 2017 Jul 12;6(7):e62.
PMID: 28698666 DOI: 10.1038/emi.2017.49

Enterovirus A71 (EV-A71) causes hand-foot-and-mouth disease (HFMD), which may be complicated by fatal encephalomyelitis. Although fecal-oral or oral-oral routes are important in person-to-person transmission, how viral shedding and exposure may predispose individuals to infection remains unknown. We investigated person-to-person transmission by using a model of HFMD and encephalomyelitis based on EV-A71 oral infection of 2-week-old hamsters. Animals (index animals) infected with 104 50% cell culture infective doses of virus uniformly developed severe disease four days post-infection (dpi), whereas littermate contacts developed severe disease after six to seven days of exposure to index animals. Virus was detected in oral washes and feces at 3-4 dpi in index animals and at three to eight days after exposure to index animals in littermate contact animals. In a second experiment, non-littermate contact animals exposed for 8 or 12 h to index animals developed the disease six and four days post-exposure, respectively. Tissues from killed index and contact animals, studied by light microscopy, immunohistochemistry and in situ hybridization, exhibited mild inflammatory lesions and/or viral antigens/RNA in the squamous epithelia of the oral cavity, tongue, paws, skin, esophagus, gastric epithelium, salivary glands, lacrimal glands, central nervous system neurons, muscles (skeletal, cardiac and smooth muscles) and liver. Orally shed viruses were probably derived from infected oral mucosa and salivary glands, whereas fecal viruses may have derived from these sites as well as from esophageal and gastric epithelia. Asymptomatic seroconversion in exposed mother hamsters was demonstrated. Our hamster model should be useful in studying person-to-person EV-A71 transmission and how drugs and vaccines may interrupt transmission.

Matched MeSH terms: Central Nervous System Infections/virology

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