Past research projects: International seed funding

Seed funding Brazil

 

Encephalitis’ clinical and laboratory characteristics during a triple epidemic of Dengue, Zika and Chikungunya

Project Lead – Aline de Moura Brasil Matos, Instituto de Medicina Tropical, Medicine School, University of São Paulo, Brazil

Awarded: 2019

Our pilot study aims to investigate clinical and laboratory aspects of 18 patients who developed encephalitis during a triple epidemics of Dengue, Zika and Chikungunya in Brazilian northeast from June 2015 to December 2017. Those people were assisted in a single tertiary center.

By that time, we asked the patients to donate blood and cerebral spinal fluid (CSF) for further virological study. As we had no funding to laboratory tests by that time, the samples were stored in an adequate facility and the patients’ clinical history was carefully noted in medical records. This initiative was approved by local ethical committee.

With funding available, we will first conduct a search for viral genetic material in those samples, though a technique called real-time polymerase chain reaction (RT-PCR).

We are also going to look into the samples for antibodies against Dengue, Zika and Chikungunya. Antibodies are specific structures from the human defense system that show us if defense was activated against an invader. They usually last from weeks to months in the host blood and CSF.

Later, we are going to measure a CSF biomarker to measure degeneration of brain cells.

Finally, we are going to compare clinical and laboratory data, to find out which virus was able to cause a larger damage and if the encephalitis was more severe when vestiges of more than one virus are present in the same patient.

If our biomarkers prove to be useful we will pursue a larger project during the patients’ one-year follow-up to evaluate if the damage caused by the viruses is only punctual or if they are able to generate a chronic and sustained brain damage.

Lead project-Aline de Moura Brasil Matos, Instituto de Medicina Tropical, Medicine School, University of São Paulo, Brazil

This seed funding has been completed.

“First of all, it was a great honour to be selected for the 2019 Encephalitis Society Seed Funding. At that time, I was starting my PhD thesis and my research had no specific funding. In my country resources are basically limited to governmental grants. In order to have one of those grants, you have to have things like published articles, international experience, a topic of public interest and supervisors recognized by their previous work.

The seed funding was essential to start my career as a young scientist and made me able to dedicate myself to my main topic of interest – neurological manifestations of emergent and re-emergent viruses in encephalitis. We started with Chikungunya virus encephalitis and our preliminary data was presented at the annual Encephalitis Society Conference.

There, I got in touch with many researchers and built relationships with them. Also, we presented this same data in several meetings in Brazil and organized a research group to gather more data about encephalitis. All of a sudden, the COVID-19 pandemic emerged, and since we were already organizing our network for neurology and viruses, we were able to direct our efforts to COVID-19. Based on this background and built network we were selected for a great national full grant to work with COVID-19 and neurology.

From June 2020 until now we followed more than 160 COVID-19 patients with neurological conditions, most of them with encephalopathy or encephalitis and hope we can soon shed some light on these manifestations.”

Dr Aline Matos, May 2021

 

Seed funding Cameroon

Aetiologies, clinical presentation and neuro-cognitive outcomes of non-HIV associated encephalitis in Cameroon – exploring a neglected disease in a low income African country

Project lead – Dr Alain Kenfak Foguena, Jura Bernois Hospital (HJB), Moutier, Switzerland and Filariasis and other Tropical Diseases Research Centre (CRFilMT), Yaoundé, Cameroon

Awarded: 2019

Acute infectious encephalitis is a frequent infectious disease associated with high mortality rates. It is caused by different etiologic agents and manifests with a wide range of clinical signs.

Encephalitis management guidelines in low- and middle-income countries (LMIC) are limited by the absence of local epidemiological data leading to delays or even absence of adequate treatment. Today’s empirical treatment based on non-specific signs and symptoms is a “blind” treatment strategy contributing to mortality. Therefore, there is an urgent need to identify the etiological agents of encephalitis in LMIC.

We intend to investigate the aetiologies and pathogen-specific elements in the clinical presentation of encephalitis in HIV-negative adults from urban and rural areas in Cameroon. To achieve this goal, we will perform microbiologic analysis on cerebrospinal fluid, as well as inflammatory, biochemical, and cerebral imaging. Additionally, we will describe survival rates, and outcomes of encephalitis in terms of physical and neuropsychological sequelae. Finally, we will associate these clinical observations with the pathogen type, initial radiologic findings.

The results will allow us to adapt diagnostic algorithms and treatment protocols to the regional variations in pathogen distribution. They will also emphasize the need for long-term follow-up and rehabilitation of survivors.

 

Seed funding Columbia University, USA

Defining the neuroinvasive potential of SARS-CoV-2 in brain autopsies of COVID-19 patients and controls

Project Lead: Dr Emily Happy Miller, Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center-New York Presbyterian Hospital

Awarded: 2020

Throughout my training I have been interested in how viruses affect their hosts. After receiving my PhD training in virology, I came to Columbia University Irving Medical Center to complete my Internal Medicine and Infectious Disease residency and fellowship training. New York City became the epicenter of the COVID-19 pandemic in the United States in Spring 2020. During this time, I helped care for patients with many different COVID-19 manifestations, including encephalopathy. I became involved with a number of research projects, including studies to better understand neurological manifestations of COVID-19.

Currently, it is unclear whether the neurological manifestations are a consequence of direct infection of the CNS by the virus or due to secondary sequelae from the virus-induced systemic inflammatory response. We have one of the largest local populations of COVID-19 patients and one of the largest collections of brain autopsies of COVID-19 patients. Analysis of the brain tissue for the virus is essential to understand whether SARS-CoV-2 affects the brain directly or indirectly. We will utilize this large collection of brain autopsy samples to determine the presence of SARS-CoV-2 in the brain by quantitative reverse transcription-PCR and viral RNA staining. Our study will elucidate possible routes of CNS infection by the virus and identify brain regions and cell types most vulnerable to either direct infection or the effects of systemic cytokines.

This seed funding from the Encephalitis Society will provide valuable support for this work in understanding the role of the virus in the brain of people who died from COVID-19. We hope that this work will help shed light on how the virus may be contributing to neurological findings in patients who are alive and dealing with COVID-19 disease. This information will be critical for thoughtful design of diagnostic tools to treat neurological complications from COVID-19 and understanding the long-term effects of the virus on the CNS.

This seed funding has now been completed. Please see below a summary of the research findings.

“Neurological signs and symptoms are known to occur in COVID-19 disease. Some of these symptoms, such as brain fog, headache and depression can linger for months. It has been largely unknown if the neurological findings are due to infection of the brain with SARS-CoV-2. Over the past several months, our group completed a large study on COVID-19 neuropathology in brain autopsies at our institution.

This multidisciplinary study involving Neuropathology, Neurology, Infectious Diseases, and Neuroradiology was recently published in the journal Brain. In the study we presented clinical, neuropathological and molecular findings from autopsies of 41 predominately Hispanic/latinx patients who died with COVID-19. Neuropathological examination revealed hypoxic/ischemic changes in all brains as well as microglial activation. Both hypoxic changes and microglial activation can lead to permanent neuronal loss.

While we found damage in the brains of these patients, we did not find significant viral infection in the brain tissue. Quantitative reverse-transcriptase PCR found low but detectable viral RNA in the majority of brains. However, this was far lower than what was found in nasal passageway tissue. Viral RNA did not correlate with the histopathological alterations seen, suggesting it is unlikely that viral infection is responsible for these changes.

Immunocytochemical staining for viral antigens and RNA in situ hybridization for viral genomic material did not find either in brain tissue, suggesting that the low RT-PCR values might have reflected viral RNA in blood vessels or leptomeninges. Future studies are needed to see if these pathological findings, which may also be present in COVID-19 survivors, contribute to any of the chronic neurological problems reported by patients. ”

Dr Emily Miller

 

Seed funding Memorial Sloan Kettering Cancer Center, USA

Dissecting the selective vulnerability of dopamine neurons to SARS-CoV-2 infection using human stem cell models

Project lead: Dr Oliver Harschnitz, The Center of Stem Cell Biology, Developmental Biology Program, Memorial Sloan Kettering Cancer Center (New York, USA)

Awarded: 2020

As a neuroimmunologist in the research group of Lorenz Studer at the Sloan Kettering Institute in New York, my work is focused on the development and application of human stem cell models to study encephalitis. Our pilot study aims to dissect the mechanisms through which subsets of neurons, specifically dopamine neurons, are susceptible to SARS-CoV-2 infection.

The present COVID-19 pandemic is a global health crisis of which we are yet to see the full effects. While infection with SARS-CoV-2 can cause severe respiratory disease and may lead to death, the late-stage pathology following SARS-CoV-2 infection remains unknown.

There is increasing evidence that viral infection may lead to neurological complications, either directly or indirectly by systemic inflammation, rendering neurons vulnerable to future stressors. One of the most famous examples is the parkinsonism that occurred subsequent to viral encephalopathy that developed following the 1918 influenza pandemic.

Human stem cell technology offers a unique opportunity to study encephalitis in a human background. Recent progress in our lab has established methods to obtain both neuronal (cortical neurons and dopamine neurons) and nonneuronal (astrocytes and microglia) cells at high purity from human pluripotent stem cells. These technological advances enable us to study the susceptibility of human brain cells to SARS-CoV-2 infection. Furthermore, it allows us to understand the SARS-CoV-2 induced interaction between neuronal and nonneuronal cells that may lead to long-term neurological damage.

The work that will be performed in this pilot study is aimed at understanding the molecular mechanisms underlying the differential susceptibility to SARS-CoV-2 in the CNS and the effect of SARS-CoV-2 infection on the function and survival of dopamine neurons. This will provide insight into the potential long-term neurological effects of COVID-19 and helps identify therapeutic targets that require additional focus for the development of neuroprotective drugs for SARS-CoV-2 infected patients.

 

Seed funding Senegal

Implementing an hospital-based encephalitis surveillance in Senegal to decipher main causes of viral encephalitis
in a West-African Low-Income Country

Project Lead – Dr Jamil Kahwagi, Clinique de Neurosciences Ibrahima Pierre Ndiaye, CHNU FANN, Dakar, SENEGAL

Awarded 2021

Lay Summary

Background: Acute meningoencephalitis is a serious disease associated with high mortality. They can be caused by
pathogens (bacteria, fungi, viruses, parasites) or of autoimmune origin. Viruses play an important role in
encephalitis, but little is known about their mode of action. A viral aetiology would be suspected in most cases, but
current diagnostic tools only allow to search for a limited number of viral agents already known.
To date, in Senegal, very little data are available on the main etiological causes of infectious meningoencephalitis.

This lack of knowledge impacts the management of patient, and it is essentially based on a probabilistic approach.
This study aims to increase our knowledge of the viral aetiologies of meningoencephalitis in Senegal.

Methods: The protocol will be part of the routine hospital management for patients with infectious
meningoencephalitis. Various biological samples will be taken, such as cerebrospinal fluids (CSF), whole blood,
oropharyngeal and nasopharyngeal swabs, and urine. In addition to the samples, socio-demographic, clinical and
exposure data will be collected in a questionnaire to describe the epidemiology of encephalitis cases and identify
potential risk factors. We will make the use of a multiplexes detection system (RT-PCR) enabling the detection of the major encephalitis-associated viruses.

Additional funds from other ongoing and future projects will extend the panel of detection to other pathogens as
well as serology assay (SARS-CoV-2), metagenomic approach and the evaluation of the use of a rapid test (lateral
flow device) by clinician and its predictive value for the orientation of bacterial vs. viral infection.

Expected results: The project will identify the main viral aetiologies associated with encephalitis, clinical description of cases, identification of risk factors and better management of infectious encephalitis.

NeuroAccess – Lusaka, Zambia 2016

Dr Michael Bonello, ST7 Neurology

The Walton Centre NHS Foundation Trust, Liverpool, UK

NeuroAccess is a project supported by The Encephalitis Society and run by Drs Benedict Michael and Sam Nightingale which aims to improve the care of patients with Encephalitis and other neurological problems in sub-Saharan Africa through improving education in clinical neurology. The project is funded by courses in neurology for UK undergraduate and postgraduate medics, and by grants from The Encephalitis Society and the Association of British Neurologists.

I would like to thank the ABN for funding my application to travel to Lusaka, Zambia between the 22nd October till the 6th November 2016. I was involved in the provision of neurological teaching as part of NeuroAccess.

NeuroAccess started in 2013, an idea of Dr Benedict Michael and Dr Sam Nightingale, where a yearly two-week course was set up to provide neurological education to general medics in the sub-Saharan African countries of Mozambique and Zambia.

Zambia is a country in southern Africa that is three times the size of the UK with a population of sixteen million people. University Teaching Hospital in Lusaka is the only government specialist referral hospital in the country and is the main centre for training local medical students and nurses.

It has basic facilities to perform blood work and CSF analysis. It has a CT scanner and currently a non-functioning MRI scanner. Work was underway to repair the MRI scanner but unfortunately, this has been ongoing for a few months. Nerve conduction services were provided by Dr Kvalsund a Neurologist who was undergoing research in HIV and B12 neuropathy.

Neurological disease has a huge prevalence causing a significant burden to the healthcare systems. There are three neurologists in the hospital. Our main contact is Dr Omar Siddiqi, who is employed by Harvard University and currently undergoing his research in Zambia. Part of his work involves providing referral services, clinics and training. He managed to set up a functioning neurophysiology lab that provides an EEG service.

The volume of work is so enormous that teaching is spread thin and thus most medics would have had insufficient neurological training. Most neurology training is provided by non-specialists and although the theoretical knowledge is of a good standard the practical application still needs improvement. The ultimate objective is to develop a cadre of local Neurologists that can carry on the work of looking after patients with neurological pathology and so much less reliant on foreign input.

Our objectives during the two-week stint were to provide basic neurological training focusing mostly on concepts of disease and pragmatic approaches to empower medical students and junior doctors currently being trained at UTH to become more versed in neurological conditions.

The course was previously delivered in Zambia in October 2013, November 2015 and Mozambique in 2014, 2015 and 2016 and in all occasions, it was very well received with excellent feedback. This was my second year going having previously travelled to Zambia in November 2015. I was accompanied by a fellow Neurology SPR and a Neurophysiologist from the Walton Centre who helped with EEG provision and further training for the two local EEG neurophysiologists.

Visit

For two weeks the day started at 07:00 with a two-hour morning teaching session delivered to the seventh year (1st week) and fourth year (2nd week) medical students in which we covered a set neurology curriculum trying to build up basic concepts like localisation to explain more complex pathology such as stroke, movement disorders and epilepsy. This was normally followed by a two-hour small group teaching session delivered to fifth-year medical students were a hands-on approach was used to highlight the concepts of the neurological history and examination. An hour session of bedside teaching with the sixth year medical students would follow. Junior Doctor teaching would be next on the agenda and this included a wide variety of teaching styles and topics. This varied from interactive lectures e.g. on neuroradiology, grand round style sessions on cerebellar disorders and spinal cord disorders, to more bedside tutorials presenting patients with Brown-Sequard syndrome and Motor Neurone Disease. A video bank of clinical signs has proved essential in making the sessions as interactive as possible. The afternoons were spent seeing inpatient referrals under the supervision of Dr Siddiqi as well as preparing the sessions for next day.

Wednesdays proved a change from the routine as after the morning 7 am lectures we made our way to the weekly neurology clinic where we would join Dr Siddiqi and Dr Kvalsund seeing patients who could have been waiting for hours and who would have travelled hundreds of miles to seek a neurology opinion. We normally used to be joined by medical students in clinic resulting in it being a teaching clinic. The feedback received for all teaching sessions was very good. Tendon hammers and pen torches were handed out to the most involved students and doctors promoting interaction. A quiz at the end of the two weeks consolidated concepts we covered all week and a diagnostic set was given to the winner.

Future plans

NeuroAccess aims to slot into a permanent program of post-graduate neurology that is currently being developed by Dr Omar Siddiqi to train a local team of Neurologists that can take forward and improve neurological care in Zambia. Its aim is to build on a strong record of teaching in the UK were faculty, teaching on the successful NeuroPACES course, have the chance to teach on the NeuroAccess course.

The programme is supported by an open access eLearning resource in neurological infection that has been developed (www.braininfectionsuk.org/neuroid_elearning) to allow future reading for junior doctors and consolidation of further knowledge. We aim to return next year to provide continuing neurological education and to build on the previous year’s teaching.

NeuroAccess is a project supported by Encephalitis International and run by Drs Benedict Michael and Sam Nightingale which aims to improve the care of patients with Encephalitis and other neurological problems in sub-Saharan Africa through improving education in clinical neurology. The project is funded by courses in neurology for UK undergraduate and postgraduate medics, and by grants from Encephalitis International and the Association of British Neurologists.

NeuroAccess, Mozambique, July 2014

Drs Benedict Michael and Sam Nightingale visited Beira Public Hospital in Mozambique between 16-27th June, 2014.

The hospital 

Beira Hospital is the second biggest hospital in Mozambique. The hospital facilities are very basic, for most of their time at the hospital there was no running water. The supply of medications is limited, and the hospital only has regular access to a single anti-epileptic medication. Infectious diseases, including Encephalitis and meningitis are a major problem. Around 20-30% of the local population is HIV positive; in the hospital around 80% have HIV. Multi-drug resistant TB is prevalent – most of the doctors and students wear protective masks on the medical wards.

Beira Hospital is staffed mostly by local doctors, but there are also doctors from Cuba, the USA and Europe. The hospital has a single neurologist from Cuba, however he is on a temporary contract and does not do any clinical teaching. The medical students and junior doctors are taught neurology by non-specialist residents. The level of theoretical knowledge of neurology amongst students is good, but their practical skills need some improvement.

Although the public hospital in Beira is extremely basic, the medical school is well set up. The first doctor has just completed a PhD, supported by a University in Germany. Her project was investigating using urine dipsticks on CSF to diagnose brain infections. As laboratory facilities are very basic this simple bedside test is very useful clinically.

Teaching

Ben and Sam taught medical students and junior doctors a daily morning session on the theory of neurological examination and diagnosis. They followed this with 4 small group bedside teaching sessions.

On the Saturday they ran an additional session at the medical school. It started with interactive cases of Encephalitis and other neurological infections. The session was completed with a neurology quiz – the winner of which received an ophthalmoscope.

The written feedback from these sessions was universally positive. Themes for suggested improvements included a request for more learning resources – eg. handouts, videos etc.

Future directions

Ben and Sam would like to support the pre-clinical undergraduate neurology teaching at the medical school which happens around April every year.

Another useful project, would be to provide videos demonstrating neurological clinical signs. On their next visit, Ben and Sam aim to record good quality footage of this and make it publicly available.

Students found the NeuroID e-learning modules useful and Ben and Sam are keen to build on this resource.

Overall, it was another successful trip. Ben and Sam are keen to continue their work, and have even more ideas for the future on how the project can develop and be more beneficial than ever!

NeuroAccess is a project supported by Encephalitis International and run by Drs Benedict Michael and Sam Nightingale which aims to improve the care of patients with Encephalitis and other neurological problems in sub-Saharan Africa through improving education in clinical neurology. The project is funded by courses in neurology for UK undergraduate and postgraduate medics, and by grants from Encephalitis International and the Association of British Neurologists.

NeuroAccess – Zambia, November 2013

Pilot trip