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1.  Controversies in HIV-associated neurocognitive disorders 
The Lancet. Neurology  2014;13(11):1139-1151.
Cross-sectional studies show that around half of individuals infected with HIV-1 have some degree of cognitive impairment despite the use of antiretroviral drugs. However, prevalence estimates vary depending on the population and methods used to assess cognitive impairment. Whether asymptomatic patients would benefit from routine screening for cognitive difficulties is unclear and the appropriate screening method and subsequent management is the subject of debate. In some patients, HIV-1 RNA can be found at higher concentrations in CSF than in blood, which potentially results from the poor distribution of antiretroviral drugs into the CNS. However, the clinical relevance of so-called CSF viral escape is not well understood. The extent to which antiretroviral drug distribution and toxicity in the CNS affect clinical decision making is also debated.
PMCID: PMC4313542  PMID: 25316020
2.  The evaluation of a tailored intervention to improve the management of suspected viral encephalitis: protocol for a cluster randomised controlled trial 
Viral encephalitis is a devastating condition for which delayed treatment is associated with increased morbidity and mortality. Clinical audits indicate substantial scope for improved detection and treatment. Improvement strategies should ideally be tailored according to identified needs and barriers to change. The aim of the study is to evaluate the effectiveness and cost-effectiveness of a tailored intervention to improve the secondary care management of suspected encephalitis.
The study is a two-arm cluster randomised controlled trial with allocation by postgraduate deanery. Participants were identified from 24 hospitals nested within 12 postgraduate deaneries in the United Kingdom (UK). We developed a multifaceted intervention package including core and flexible components with embedded behaviour change techniques selected on the basis of identified needs and barriers to change. The primary outcome will be a composite of the proportion of patients with suspected encephalitis receiving timely and appropriate diagnostic lumbar puncture within 12 h of hospital admission and aciclovir treatment within 6 h. We will gather outcome data pre-intervention and up to 12 months post-intervention from patient records. Statistical analysis at the cluster level will be blind to allocation. An economic evaluation will estimate intervention cost-effectiveness from the health service perspective.
Trial registration
Controlled Trials: ISRCTN06886935.
Electronic supplementary material
The online version of this article (doi:10.1186/s13012-014-0201-1) contains supplementary material, which is available to authorized users.
PMCID: PMC4314797  PMID: 25623603
Encephalitis; Cluster randomised controlled trial; Guideline implementation; Protocol
3.  Neuropathogenesis of Japanese Encephalitis in a Primate Model 
Japanese encephalitis (JE) is a major cause of mortality and morbidity for which there is no treatment. In addition to direct viral cytopathology, the inflammatory response is postulated to contribute to the pathogenesis. Our goal was to determine the contribution of bystander effects and inflammatory mediators to neuronal cell death.
Methodology/Principal Findings
Material from a macaque model was used to characterize the inflammatory response and cytopathic effects of JE virus (JEV). Intranasal JEV infection induced a non-suppurative encephalitis, dominated by perivascular, infiltrates of mostly T cells, alongside endothelial cell activation, vascular damage and blood brain barrier (BBB) leakage; in the adjacent parenchyma there was macrophage infiltration, astrocyte and microglia activation. JEV antigen was mostly in neurons, but there was no correlation between intensity of viral infection and degree of inflammatory response. Apoptotic cell death occurred in both infected and non-infected neurons. Interferon-α, which is a microglial activator, was also expressed by both. Tumour Necrosis Factor-α, inducible nitric oxide synthase and nitrotyrosine were expressed by microglial cells, astrocytes and macrophages. The same cells expressed matrix metalloproteinase (MMP)-2 whilst MMP-9 was expressed by neurons.
The results are consistent with JEV inducing neuronal apoptotic death and release of cytokines that initiate microglial activation and release of pro-inflammatory and apoptotic mediators with subsequent apoptotic death of both infected and uninfected neurons. Activation of astrocytes, microglial and endothelial cells likely contributes to inflammatory cell recruitment and BBB breakdown. It appears that neuronal apoptotic death and activation of microglial cells and astrocytes play a crucial role in the pathogenesis of JE.
Author Summary
Japanese encephalitis (JE) is one of the most important causes of viral encephalitis worldwide, with no specific antiviral treatment available. Despite some recent successes with widespread vaccination, JE will likely remain an important public health problem; because the virus is mosquito-borne and has natural animal hosts, it will never be eradicated. We have little understanding of what determines the severity and outcome of infection. Data from human post mortem studies is very limited because of cultural constraints on autopsies in areas where JE occurs. Circumstantial evidence suggests that in addition to cytopathology caused directly by infection of neurons, there may be bystander cell death of non-infected neurons, caused by an excessive inflammatory response. Our study used archived brain samples from a prior challenge study in a validated macaque model of JE. We stained for the presence of JEV antigen, apoptosis, and pro-inflammatory markers in affected areas, such as the thalamus and brainstem. We show that bystander neuronal cell death is important, and elucidate the inflammatory and apoptotic mechanisms underlying it. Currently there is no proven efficacious therapy for most viral infections of the central nervous system, including JE. Novel strategies for treating such infections are urgently needed. Our findings suggest new anti-inflammatory and anti-apoptotic therapeutic approaches may be useful in treating this debilitating disease.
PMCID: PMC4125110  PMID: 25102067
4.  HIV Associated Neurocognitive Disorders (HAND) in Malawian Adults and Effect on Adherence to Combination Anti-Retroviral Therapy: A Cross Sectional Study 
PLoS ONE  2014;9(6):e98962.
Little is known about the prevalence and burden of HIV associated neurocognitive disorder (HAND) among patients on combination antiretroviral therapy (cART) in sub-Saharan Africa. We estimated the prevalence of HAND in adult Malawians on cART and investigated the relationship between HAND and adherence to cART.
HIV positive adults in Blantyre, Malawi underwent a full medical history, neurocognitive test battery, depression score, Karnofsky Performance Score and adherence assessment. The Frascati criteria were used to diagnose HAND and the Global Deficit Score (GDS) was also assessed. Blood was drawn for CD4 count and plasma nevirapine and efavirenz concentrations. HIV negative adults were recruited from the HIV testing clinic to provide normative scores for the neurocognitive battery.
One hundred and six HIV positive patients, with median (range) age 39 (18–71) years, 73% female and median (range) CD4 count 323.5 (68–1039) cells/µl were studied. Symptomatic neurocognitive impairment was present in 15% (12% mild neurocognitive disorder [MND], 3% HIV associated dementia [HAD]). A further 55% fulfilled Frascati criteria for asymptomatic neurocognitive impairment (ANI); however factors other than neurocognitive impairment could have confounded this estimate. Neither the symptomatic (MND and HAD) nor asymptomatic (ANI) forms of HAND were associated with subtherapeutic nevirapine/efavirenz concentrations, adjusted odds ratio 1.44 (CI. 0.234, 8.798; p = 0.696) and aOR 0.577 (CI. 0.09, 3.605; p = 0.556) respectively. All patients with subtherapeutic nevirapine/efavirenz levels had a GDS of less than 0.6, consistent with normal neurocognition.
Fifteen percent of adult Malawians on cART had a diagnosis of MND or HAD. Subtherapeutic drug concentrations were found exclusively in patients with normal neurocognitive function suggesting HAND did not affect cART adherence. Further study of HAND requires more robust locally derived normative neurocognitive values and determination of the clinical relevance of ANI.
PMCID: PMC4051684  PMID: 24915530
5.  The British antibiotic and silver-impregnated catheters for ventriculoperitoneal shunts multi-centre randomised controlled trial (the BASICS trial): study protocol 
Trials  2014;15:4.
Insertion of a ventriculoperitoneal shunt (VPS) for the treatment of hydrocephalus is one of the most common neurosurgical procedures in the UK, but failures caused by infection occur in approximately 8% of primary cases. VPS infection is associated with considerable morbidity and mortality and its management results in substantial cost to the health service. Antibiotic-impregnated (rifampicin and clindamycin) and silver-impregnated VPS have been developed to reduce infection rates. Whilst there is some evidence showing that such devices may lead to a reduction in VPS infection, there are no randomised controlled trials (RCTs) to support their routine use.
Overall, 1,200 patients will be recruited from 17 regional neurosurgical units in the UK and Ireland. Patients of any age undergoing insertion of their first VPS are eligible. Patients with previous indwelling VPS, active and on-going cerebrospinal fluid (CSF) or peritoneal infection, multiloculated hydrocephalus requiring multiple VPS or neuroendoscopy, and ventriculoatrial or ventriculopleural shunt planned will be excluded. Patients will be randomised 1:1:1 to either standard silicone (comparator), antibiotic-impregnated, or silver-impregnated VPS. The primary outcome measure is time to VPS infection. Secondary outcome measures include time to VPS failure of any cause, reason for VPS failure (infection, mechanical failure, or patient failure), types of bacterial VPS infection (organism type and antibiotic resistance), and incremental cost per VPS failure averted.
The British antibiotic and silver-impregnated catheters for ventriculoperitoneal shunts multi-centre randomised controlled trial (the BASICS trial) is the first multi-centre RCT designed to determine whether antibiotic or silver-impregnated VPS reduce early shunt infection compared to standard silicone VPS. The results of this study will be used to inform current neurosurgical practice and may potentially benefit patients undergoing shunt surgery in the future.
Trial registration
International Standard Randomised Controlled Trial Number: ISRCTN49474281.
PMCID: PMC3892025  PMID: 24383496
Ventriculoperitoneal shunt; Infection; Clinical trial; Antibiotic-impregnated; Silver-impregnated
6.  The Functional, Social and Economic Impact of Acute Encephalitis Syndrome in Nepal – a Longitudinal Follow-Up Study 
Over 133,000 children present to hospitals with Acute Encephalitis Syndrome (AES) annually in Asia. Japanese encephalitis (JE) accounts for approximately one-quarter of cases; in most cases no pathogen is identified and management is supportive. Although JE is known to result in neurological impairment, few studies have examined the wider impact of JE and AES on patients and their families.
Methodology/Principal Findings
Children (aged 1 month–14 years) with AES were assessed 5–12 months after discharge from two Nepali hospitals. Assessment included clinical examination, the Liverpool Outcome Score (LOS) - a validated assessment of function following encephalitis, questionnaires about the child's social participation since discharge, and out-of-pocket costs to the family. Children were classified as JE or ‘other AES’ based on anti-JE virus antibody titres during acute illness. Contact was made with the families of 76% (73/96) of AES children. Six children had died and one declined participation. 48% (32/66) reported functional impairment at follow-up, most frequently affecting behaviour, language or limb use. Impairment was more frequent in JE compared to ‘other AES’ cases (68% [13/19] versus 40% [19/47]; p = 0.06). 49% (26/53) had improvement in LOS between discharge and follow-up. The median out-of-pocket cost to families, including medical bills, medication and lost earnings was US$ 1151 (10 times their median monthly income) for children with severe/moderate impairment and $524 (4.6 times their income) for those with mild/no impairment (P = 0.007). Acute admission accounted for 74% of costs. Social participation was limited in 21% of children (n = 14).
Prolonged functional impairment was common following AES. Economic impact to families was substantial. Encouragingly, almost half the children improved after discharge and most reported sustained social participation. This study highlights a need for long-term medical support following AES. Rationalisation of initial expensive hospital treatments may be warranted, especially since only supportive treatment is available.
Author Summary
More than 133,000 children present annually to hospitals in Asia with clinical features of acute brain infection (Acute Encephalitis Syndrome [AES]). Japanese encephalitis accounts for one-quarter of cases in Asia. With no specific treatments for AES, management is largely supportive. AES commonly causes neurological problems. However, few studies have examined long-term outcome or the economic cost of AES. We followed up 72 Nepali children 5–12 months after acute hospital admission for AES and studied their neurological function, social participation and the out-of-pocket costs to the family. At follow-up, 6 children had died and 48% of survivors had impaired function. Behaviour, language or limb impairments were common. Encouragingly, almost half the children reported improved function at follow-up compared to hospital discharge. The economic impact was substantial; $1151 US dollars (10 times their monthly income) among families with children suffering severe/moderate impairment. Acute admission represented 74% of total costs. Few families reported limitations in their child's social participation. The functional problems experienced by these children highlights their need for long-term medical support. The substantial economic costs to families suggest rationalisation of acute care costs may be warranted. Families reported their child maintaining social participation, implying a positive attitude to social engagement.
PMCID: PMC3772013  PMID: 24069467
7.  Viral CNS infections in children from a malaria-endemic area of Malawi: a prospective cohort study 
The Lancet Global Health  2013;1(3):e153-e160.
Fever with reduced consciousness is an important cause of hospital admission of children in sub-Saharan Africa, with high mortality. Cerebral malaria, diagnosed when acute Plasmodium falciparum infection and coma are recorded with no other apparent reason, is one important cause. We investigated whether viruses could also be an important cause of CNS infection in such patients, and examined the relative contribution of viral pathogens and malaria parasitaemia.
We did a prospective cohort study in Blantyre, Malawi. From March 1, 2002, to Aug 31, 2004, we enrolled children aged between 2 months and 15 years who were admitted to hospital with suspected non-bacterial CNS infections. Children with a cerebrospinal fluid (CSF) white cell count of less than 1000 cells per μL and negative bacterial microscopy and culture were deemed to have suspected viral CNS infection. Blood was examined for asexual forms of P falciparum. PCR was done on CSF or on post-mortem brain biopsy specimens to detect 15 viruses known to cause CNS infection.
Full outcome data were available for 513 children with suspected viral CNS infection, of whom 94 (18%) died. 163 children (32%) had P falciparum parasitaemia, of whom 34 (21%) died. At least one virus was detected in the CNS in 133 children (26%), of whom 43 (33%) died. 12 different viruses were detected; adenovirus was the most common, affecting 42 children; mumps, human herpes virus 6, rabies, cytomegalovirus, herpes simplex virus 1, and enterovirus were also important. 45 (9%) of the 513 children had both parasitaemia and viral infection, including 27 (35%) of 78 diagnosed clinically with cerebral malaria. Children with dual infection were more likely to have seizures than were those with parasitaemia alone, viral infection only, or neither (p<0·0001). 17 (38%) of the 45 children with dual infection died, compared with 26 (30%) of 88 with viral infection only, 17 (14%) of 118 with parasitaemia only, and 34 (13%) of 262 with neither (p<0·0001). Logistic regression showed children with a viral CNS infection had a significantly higher mortality than did those who did not have a viral CNS infection (p=0·001).
Viral CNS infections are an important cause of hospital admission and death in children in Malawi, including in children whose coma might be attributed solely to cerebral malaria. Interaction between viral infection and parasitaemia could increase disease severity.
Wellcome Trust, US National Institutes of Health, and UK Medical Research Council.
PMCID: PMC3986031  PMID: 24748325
8.  The Effect of Vaccination Coverage and Climate on Japanese Encephalitis in Sarawak, Malaysia 
Japanese encephalitis (JE) is the leading cause of viral encephalitis across Asia with approximately 70,000 cases a year and 10,000 to 15,000 deaths. Because JE incidence varies widely over time, partly due to inter-annual climate variability effects on mosquito vector abundance, it becomes more complex to assess the effects of a vaccination programme since more or less climatically favourable years could also contribute to a change in incidence post-vaccination. Therefore, the objective of this study was to quantify vaccination effect on confirmed Japanese encephalitis (JE) cases in Sarawak, Malaysia after controlling for climate variability to better understand temporal dynamics of JE virus transmission and control.
Methodology/principal findings
Monthly data on serologically confirmed JE cases were acquired from Sibu Hospital in Sarawak from 1997 to 2006. JE vaccine coverage (non-vaccine years vs. vaccine years) and meteorological predictor variables, including temperature, rainfall and the Southern Oscillation index (SOI) were tested for their association with JE cases using Poisson time series analysis and controlling for seasonality and long-term trend. Over the 10-years surveillance period, 133 confirmed JE cases were identified. There was an estimated 61% reduction in JE risk after the introduction of vaccination, when no account is taken of the effects of climate. This reduction is only approximately 45% when the effects of inter-annual variability in climate are controlled for in the model. The Poisson model indicated that rainfall (lag 1-month), minimum temperature (lag 6-months) and SOI (lag 6-months) were positively associated with JE cases.
This study provides the first improved estimate of JE reduction through vaccination by taking account of climate inter-annual variability. Our analysis confirms that vaccination has substantially reduced JE risk in Sarawak but this benefit may be overestimated if climate effects are ignored.
Author Summary
Japanese encephalitis (JE) virus is a mosquito-borne virus which is the leading cause of viral encephalitis in Asia. The cumulative attack rate for human JE cases is seemingly low (2-cases/105/year); however, epidemics are focal and intense, being concentrated in children 1 to 15 years of age and highly clustered spatially. Despite the availability of a vaccine against JE virus (JEV), a significant number of JE cases still occur in Asia. Increases in disease cases may occur in some countries, such as Indonesia and Bangladesh, due to increasing rice cultivation, pig husbandry and lack of vaccination or vector control programs in these areas. However, given the sensitivity of JEV transmission to climate through impacts on the mosquito vectors, changes in climate may increase or decrease JEV transmission. Clearly, JE vaccination has substantially reduced JE cases, but it is not clear if climate has any confounding impact on our ability to estimate vaccine effect. We found that approximately one quarter of the reduction in JE cases since vaccination was introduced might be attributable to climatically unfavourable years for the disease, rather than the effect of vaccination. Vaccination studies involving climate-sensitive diseases may be made more accurate by taking climate effects into account.
PMCID: PMC3738455  PMID: 23951373
9.  HIV infection and stroke: current perspectives and future directions 
Lancet Neurology  2012;11(10):878-890.
HIV infection can result in stroke via several mechanisms, including opportunistic infection, vasculopathy, cardioembolism, and coagulopathy. However, the occurrence of stroke and HIV infection might often be coincidental. HIV-associated vasculopathy describes various cerebrovascular changes, including stenosis and aneurysm formation, vasculitis, and accelerated atherosclerosis, and might be caused directly or indirectly by HIV infection, although the mechanisms are controversial. HIV and associated infections contribute to chronic inflammation. Combination antiretroviral therapies (cART) are clearly beneficial, but can be atherogenic and could increase stroke risk. cART can prolong life, increasing the size of the ageing population at risk of stroke. Stroke management and prevention should include identification and treatment of the specific cause of stroke and stroke risk factors, and judicious adjustment of the cART regimen. Epidemiological, clinical, biological, and autopsy studies of risk, the pathogenesis of HIV-associated vasculopathy (particularly of arterial endothelial damage), the long-term effects of cART, and ideal stroke treatment in patients with HIV are needed, as are antiretrovirals that are without vascular risk.
PMCID: PMC3460367  PMID: 22995692
10.  Suboptimal management of central nervous system infections in children: a multi-centre retrospective study 
BMC Pediatrics  2012;12:145.
We aimed to audit the regional management of central nervous system (CNS) infection in children.
The study was undertaken in five district general hospitals and one tertiary paediatric hospital in the Mersey region of the UK. Children admitted to hospital with a suspected CNS infection over a three month period were identified. Children were aged between 4 weeks and 16 years old. Details were recorded from the case notes and electronic records. We measured the appropriateness of management pathways as outlined by national and local guidelines.
Sixty-five children were identified with a median age of 6 months (range 1 month to 15 years). Ten had a CNS infection: 4 aseptic meningitis, 3 purulent meningitis, 3 encephalitis [2 with herpes simplex virus (HSV) type 1]. A lumbar puncture (LP) was attempted in 50 (77%) cases but only 43 had cerebrospinal fluid (CSF) available for analysis. Of these 24 (57%) had a complete standard set of tests performed. Fifty eight (89%) received a third generation cephalosporin. Seventeen (26%) also received aciclovir with no obvious indication in 9 (53%). Only 11 (65%) of those receiving aciclovir had CSF herpes virus PCR. Seventeen had cranial imaging and it was the first management step in 14. Treatment lengths of both antibiotics and aciclovir were highly variable: one child with HSV encephalitis was only treated with aciclovir for 7 days.
The clinical management of children with suspected CNS infections across the Mersey region is heterogeneous and often sub-optimal, particularly for the investigation and treatment of viral encephalitis. National guidelines for the management of viral encephalitis are needed.
PMCID: PMC3443041  PMID: 22958329
Encephalitis; Meningitis; Central nervous system infection; Aciclovir; Lumbar puncture
11.  Flavivirus-induced antibody cross-reactivity 
The Journal of General Virology  2011;92(Pt 12):2821-2829.
Dengue viruses (DENV) cause countless human deaths each year, whilst West Nile virus (WNV) has re-emerged as an important human pathogen. There are currently no WNV or DENV vaccines licensed for human use, yet vaccines exist against other flaviviruses. To investigate flavivirus cross-reactivity, sera from a human cohort with a history of vaccination against tick-borne encephalitis virus (TBEV), Japanese encephalitis virus (JEV) and yellow fever virus (YFV) were tested for antibodies by plaque reduction neutralization test. Neutralization of louping ill virus (LIV) occurred, but no significant neutralization of Murray Valley encephalitis virus was observed. Sera from some individuals vaccinated against TBEV and JEV neutralized WNV, which was enhanced by YFV vaccination in some recipients. Similarly, some individuals neutralized DENV-2, but this was not significantly influenced by YFV vaccination. Antigenic cartography techniques were used to generate a geometric illustration of the neutralization titres of selected sera against WNV, TBEV, JEV, LIV, YFV and DENV-2. This demonstrated the individual variation in antibody responses. Most sera had detectable titres against LIV and some had titres against WNV and DENV-2. Generally, LIV titres were similar to titres against TBEV, confirming the close antigenic relationship between TBEV and LIV. JEV was also antigenically closer to TBEV than WNV, using these sera. The use of sera from individuals vaccinated against multiple pathogens is unique relative to previous applications of antigenic cartography techniques. It is evident from these data that notable differences exist between amino acid sequence identity and mapped antigenic relationships within the family Flaviviridae.
PMCID: PMC3352572  PMID: 21900425
12.  Epstein-Barr Virus Coinfection in Cerebrospinal Fluid Is Associated With Increased Mortality in Malawian Adults With Bacterial Meningitis 
The Journal of Infectious Diseases  2011;205(1):106-110.
Mortality from adult bacterial meningitis exceeds 50% in sub-Saharan Africa. We postulated that—particularly in individuals infected with human immunodeficiency virus (HIV)—herpes simplex virus, varicella zoster virus, Epstein-Barr virus (EBV), and cytomegalovirus (CMV) in the cerebrospinal fluid (CSF) contribute to poor outcome. CSF from 149 Malawian adults with bacterial meningitis and 39 controls were analyzed using polymerase chain reaction. EBV was detected in 79 of 149 bacterial meningitis patients. Mortality (54%) was associated with higher CSF EBV load when adjusted for HIV (P = .01). CMV was detected in 11 of 115 HIV-infected patients, 8 of whom died. The mechanisms by which EBV and CMV contribute to poor outcome require further investigation.
PMCID: PMC3242746  PMID: 22075766
13.  Clinical and prognostic features among children with acute encephalitis syndrome in Nepal; a retrospective study 
BMC Infectious Diseases  2011;11:294.
Acute encephalitis syndrome (AES) is commonly seen among hospitalized Nepali children. Japanese Encephalitis (JE) accounts for approximately one-quarter of cases. Although poor prognostic features for JE have been identified, and guide management, relatively little is reported on the remaining three-quarters of AES cases.
Children with AES (n = 225) were identified through admission records from two hospitals in Kathmandu between 2006 and 2008. Patients without available lumbar puncture results (n = 40) or with bacterial or plasmodium infection (n = 40) were analysed separately. The remaining AES patients with suspected viral aetiology were classified, based on positive IgM antibody in serum or cerebral spinal fluid, as JE (n = 42) or AES of unknown viral aetiology (n = 103); this latter group was sub-classified into Non-JE (n = 44) or JE status unknown (n = 59). Bad outcome was defined as death or neurological sequelae at discharge.
AES patients of suspected viral aetiology more frequently had a bad outcome than those with bacterial or plasmodium infection (31% versus 13%; P = 0.039). JE patients more frequently had a bad outcome than those with AES of unknown viral aetiology (48% versus 24%; P = 0.01). Bad outcome was independently associated in both JE and suspected viral aetiology groups with a longer duration of fever pre-admission (P = 0.007; P = 0.002 respectively) and greater impairment of consciousness (P = 0.02; P < 0.001). A higher proportion of JE patients presented with a focal neurological deficit compared to patients of unknown viral aetiology (13/40 versus 11/103; P = 0.005). JE patients weighed less (P = 0.03) and exhibited a higher respiratory rate (P = 0.003) compared to Non-JE patients.
Nepali children with AES of suspected viral aetiology or with JE frequently suffered a bad outcome. Despite no specific treatment, patients who experienced a shorter duration of fever before hospital admission more frequently recovered completely. Prompt referral may allow AES patients to receive potentially life-saving supportive management. Previous studies have indicated supportive management, such as fluid provision, is associated with better outcome in JE. The lower weight and higher respiratory rate among JE patients may reflect multiple clinical complications, including dehydration. The findings suggest a more systematic investigation of the influence of supportive management on outcome in AES is warranted.
PMCID: PMC3219745  PMID: 22035278
14.  Recombination and positive selection identified in complete genome sequences of Japanese encephalitis virus 
Archives of Virology  2011;157(1):75-83.
The mosquito-borne Japanese encephalitis virus (JEV) causes encephalitis in man but not in pigs. Complete genomes of a human, mosquito and pig isolate from outbreaks in 1982 and 1985 in Thailand were sequenced with the aim of identifying determinants of virulence that may explain the differences in outcomes of JEV infection between pigs and man. Phylogenetic analysis revealed that five of these isolates belonged to genotype I, but the 1982 mosquito isolate belonged to genotype III. There was no evidence of recombination among the Thai isolates, but there were phylogenetic signals suggestive of recombination in a 1994 Korean isolate (K94P05). Two sites of the genome under positive selection were identified: codons 996 and 2296 (amino acids 175 of the non-structural protein NS1 and 24 of NS4B, respectively). A structurally significant substitution was seen at NS4B position 24 of the human isolate compared with the mosquito and pig isolates from the 1985 outbreak in Thailand. The potential importance of the two sites in the evolution and ecology of JEV merits further investigation.
Electronic supplementary material
The online version of this article (doi:10.1007/s00705-011-1143-4) contains supplementary material, which is available to authorized users.
PMCID: PMC3249550  PMID: 22033595
15.  Human Parvovirus 4 as Potential Cause of Encephalitis in Children, India 
Emerging Infectious Diseases  2011;17(8):1484-1487.
To investigate whether uncharacterized infectious agents were associated with neurologic disease, we analyzed cerebrospinal fluid specimens from 12 children with acute central nervous system infection. A high-throughput pyrosequencing screen detected human parvovirus 4 DNA in cerebrospinal fluid of 2 children with encephalitis of unknown etiology.
PMCID: PMC3381555  PMID: 21801629
viruses; human parvovirus; high throughput sequencing; PARV4; encephalitis; epidemiology; pediatrics; children; India; dispatch
16.  The Spatial Heterogeneity between Japanese Encephalitis Incidence Distribution and Environmental Variables in Nepal 
PLoS ONE  2011;6(7):e22192.
To identify potential environmental drivers of Japanese Encephalitis virus (JE) transmission in Nepal, we conducted an ecological study to determine the spatial association between 2005 Nepal JE incidence, and climate, agricultural, and land-cover variables at district level.
District-level data on JE cases were examined using Local Indicators of Spatial Association (LISA) analysis to identify spatial clusters from 2004 to 2008 and 2005 data was used to fit a spatial lag regression model with climate, agriculture and land-cover variables.
Prior to 2006, there was a single large cluster of JE cases located in the Far-West and Mid-West terai regions of Nepal. After 2005, the distribution of JE cases in Nepal shifted with clusters found in the central hill areas. JE incidence during the 2005 epidemic had a stronger association with May mean monthly temperature and April mean monthly total precipitation compared to mean annual temperature and precipitation. A parsimonious spatial lag regression model revealed, 1) a significant negative relationship between JE incidence and April precipitation, 2) a significant positive relationship between JE incidence and percentage of irrigated land 3) a non-significant negative relationship between JE incidence and percentage of grassland cover, and 4) a unimodal non-significant relationship between JE Incidence and pig-to-human ratio.
JE cases clustered in the terai prior to 2006 where it seemed to shift to the Kathmandu region in subsequent years. The spatial pattern of JE cases during the 2005 epidemic in Nepal was significantly associated with low precipitation and the percentage of irrigated land. Despite the availability of an effective vaccine, it is still important to understand environmental drivers of JEV transmission since the enzootic cycle of JEV transmission is not likely to be totally interrupted. Understanding the spatial dynamics of JE risk factors may be useful in providing important information to the Nepal immunization program.
PMCID: PMC3141013  PMID: 21811573
17.  Enterovirus 75 Encephalitis in Children, Southern India 
Emerging Infectious Diseases  2010;16(11):1780-1782.
Recent outbreaks of enterovirus in Southeast Asia emphasize difficulties in diagnosis of this infection. To address this issue, we report 5 (4.7%) children infected with enterovirus 75 among 106 children with acute encephalitis syndrome during 2005–2007 in southern India. Throat swab specimens may be useful for diagnosis of enterovirus 75 infection.
PMCID: PMC3294525  PMID: 21029544
Enterovirus 75; viruses; encephalitis; children; diagnostics; India; dispatch
18.  Evidence and rationale for the World Health Organization recommended standards for Japanese encephalitis surveillance 
Japanese encephalitis (JE) is the most important form of viral encephalitis in Asia. Surveillance for the disease in many countries has been limited. To improve collection of accurate surveillance data in order to increase understanding of the full impact of JE and monitor control programs, World Health Organization (WHO) Recommended Standards for JE Surveillance have been developed. To aid acceptance of the Standards, we describe the process of development, provide the supporting evidence, and explain the rationale for the recommendations made in the document.
A JE Core Working Group was formed in 2002 and worked on development of JE surveillance standards. A series of questions on specific topics was initially developed. A literature review was undertaken and the findings were discussed and documented. The group then prepared a draft document, with emphasis placed on the feasibility of implementation in Asian countries. A field test version of the Standards was published by WHO in January 2006. Feedback was then sought from countries that piloted the Standards and from public health professionals in forums and individual meetings to modify the Standards accordingly.
After revisions, a final version of the JE surveillance standards was published in August 2008. The supporting information is presented here together with explanations of the rationale and levels of evidence for specific recommendations.
Provision of the supporting evidence and rationale should help to facilitate successful implementation of the JE surveillance standards in JE-endemic countries which will in turn enable better understanding of disease burden and the impact of control programs.
PMCID: PMC2809064  PMID: 20038298
19.  Breaching the Barrier and Inflaming Epilepsy Research 
Epilepsy Currents  2009;9(5):148-150.
PMCID: PMC2759050  PMID: 19826510
20.  Chikungunya Virus and Central Nervous System Infections in Children, India 
Emerging Infectious Diseases  2009;15(2):329-331.
Chikungunya virus (CHIKV) is a mosquito-borne alphavirus best known for causing fever, rash, arthralgia, and occasional neurologic disease. By using real-time reverse transcription–PCR, we detected CHIKV in plasma samples of 8 (14%) of 58 children with suspected central nervous system infection in Bellary, India. CHIKV was also detected in the cerebrospinal fluid of 3 children.
PMCID: PMC2662654  PMID: 19193287
chikungunya virus; central nervous system viral diseases; polymerase chain reaction; incidence; Japanese encephalitis vaccines; encephalitis; Japanese; dispatch
21.  Identification and validation of clinical predictors for the risk of neurological involvement in children with hand, foot, and mouth disease in Sarawak 
Human enterovirus 71 (HEV71) can cause Hand, foot, and mouth disease (HFMD) with neurological complications, which may rapidly progress to fulminant cardiorespiratory failure, and death. Early recognition of children at risk is the key to reduce acute mortality and morbidity.
We examined data collected through a prospective clinical study of HFMD conducted between 2000 and 2006 that included 3 distinct outbreaks of HEV71 to identify risk factors associated with neurological involvement in children with HFMD.
Total duration of fever ≥ 3 days, peak temperature ≥ 38.5°C and history of lethargy were identified as independent risk factors for neurological involvement (evident by CSF pleocytosis) in the analysis of 725 children admitted during the first phase of the study. When they were validated in the second phase of the study, two or more (≥ 2) risk factors were present in 162 (65%) of 250 children with CSF pleocytosis compared with 56 (30%) of 186 children with no CSF pleocytosis (OR 4.27, 95% CI2.79–6.56, p < 0.0001). The usefulness of the three risk factors in identifying children with CSF pleocytosis on hospital admission during the second phase of the study was also tested. Peak temperature ≥ 38.5°C and history of lethargy had the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of 28%(48/174), 89%(125/140), 76%(48/63) and 50%(125/251), respectively in predicting CSF pleocytosis in children that were seen within the first 2 days of febrile illness. For those presented on the 3rd or later day of febrile illness, the sensitivity, specificity, PPV and NPV of ≥ 2 risk factors predictive of CSF pleocytosis were 75%(57/76), 59%(27/46), 75%(57/76) and 59%(27/46), respectively.
Three readily elicited clinical risk factors were identified to help detect children at risk of neurological involvement. These risk factors may serve as a guide to clinicians to decide the need for hospitalization and further investigation, including cerebrospinal fluid examination, and close monitoring for disease progression in children with HFMD.
PMCID: PMC2637878  PMID: 19152683
22.  Recurrent myositis triggered by infections: a case report 
Recurrent myositis triggered by infections is unusual, with only one other case reporting two attacks described in the literature.
Case presentation
We report the case of a 24-year-old Caucasian woman with recurrent myositis triggered by sore throat, respiratory and urinary tract infections, over the past 18 years, up to four times a year. Myositis of this frequency and duration, apparently triggered by infections, has not been reported previously.
We believe that this case adds to the understanding of myositis associated with infections being a triggered autoimmune response, and postulate that the pathogenesis in our patient is a non-specific immune response to a range of different precipitants, both bacterial and viral.
PMCID: PMC2588625  PMID: 19014567
23.  The incidence of acute encephalitis syndrome in Western industrialised and tropical countries 
Virology Journal  2008;5:134.
As part of efforts to control Japanese encephalitis (JE), the World Health Organization is producing a set of standards for JE surveillance, which require the identification of patients with acute encephalitis syndrome (AES). This review aims to provide information to determine what minimum annual incidence of AES should be reported to show that the surveillance programme is active.
A total of 12,436 articles were retrieved from 3 databases; these were screened by title search and duplicates removed to give 1,083 papers which were screened by abstract (or full paper if no abstract available) to give 87 papers. These 87 were reviewed and 25 papers identified which met the inclusion criteria.
Case definitions and diagnostic criteria, aetiologies, study types and reliability varied among the studies reviewed. Amongst prospective studies reviewed from Western industrialised settings, the range of incidences of AES one can expect was 10.5–13.8 per 100,000 for children. For adults only, the minimum incidence from the most robust prospective study from a Western setting gave an incidence of 2.2 per 100,000. The incidence from the two prospective studies for all age groups was 6.34 and 7.4 per 100,000 from a tropical and a Western setting, respectively. However, both studies included arboviral encephalitis, which may have given higher rather than given higher] incidence levels.
In the most robust, prospective studies conducted in Western industrialised countries, a minimum incidence of 10.5 per 100,000 AES cases was reported for children and 2.2 per 100,000 for adults. The minimum incidence for all ages was 6.34 per 100,000 from a tropical setting. On this basis, for ease of use in protocols and for future WHO surveillance standards, a minimum incidence of 10 per 100,000 AES cases is suggested as an appropriate target for studies of children alone and 2 per 100,000 for adults and 6 per 100,000 for all age groups.
PMCID: PMC2583971  PMID: 18973679
24.  Evaluation of Different Clinical Sample Types in Diagnosis of Human Enterovirus 71-Associated Hand-Foot-and-Mouth Disease▿  
Journal of Clinical Microbiology  2007;45(6):1858-1866.
Human enterovirus 71 and coxsackievirus A16 are important causes of hand-foot-and-mouth disease (HFMD). Like other enteroviruses, they can be isolated from a range of sterile and nonsterile sites, but which clinical sample, or combination of samples, is the most useful for laboratory diagnosis of HFMD is not clear. We attempted virus culture for 2,916 samples from 628 of 725 children with HFMD studied over a 3 1/2-year period, which included two large outbreaks. Overall, throat swabs were the single most useful specimen, being positive for any enterovirus for 288 (49%) of 592 patients with a full set of samples. Vesicle swabs were positive for 169 (48%) of 333 patients with vesicles, the yield being greater if two or more vesicles were swabbed. The combination of throat plus vesicle swabs enabled the identification of virus for 224 (67%) of the 333 patients with vesicles; for this patient group, just 27 (8%) extra patients were diagnosed when rectal and ulcer swabs were added. Of 259 patients without vesicles, use of the combination of throat plus rectal swab identified virus for 138 (53%). For 60 patients, virus was isolated from both vesicle and rectal swabs, but for 12 (20%) of these, the isolates differed. Such discordance occurred for just 11 (10%) of 112 patients with virus isolated from vesicle and throat swabs. During large HFMD outbreaks, we suggest collecting swabs from the throat plus one other site: vesicles, if these are present (at least two should be swabbed), or the rectum if there are no vesicles. Vesicle swabs give a high diagnostic yield, with the added advantage of being from a sterile site.
PMCID: PMC1933032  PMID: 17446325
25.  Rabies Encephalitis in Malaria-Endemic Area, Malawi, Africa 
Emerging Infectious Diseases  2007;13(1):136-139.
In a malaria-endemic area of Africa, rabies was an important cause of fatal central nervous system infection, responsible for 14 (10.5%) of 133 cases. Four patients had unusual clinical manifestations, and rabies was only diagnosed postmortem. Three (11.5%) of 26 fatal cases were originally attributed to cerebral malaria.
PMCID: PMC2725806  PMID: 17370529
Rabies; central nervous system infection; Malaria; zoonosis; dispatch

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