International #ANEawareness Day
31st July 2018
Join Us and help us to Raise Awareness of
Acute Necrotizing Encephalopathy
ANE International believes that raising awareness of Acute Necrotizing Encephalopathy will save lives.
With initial symptoms being typical of viral illness and many cases being from influenza, many ANE patients are initially turned away from hospital emergency rooms.
In most cases the patient is already showing unusual symptoms which are overlooked.
These may include double vision, unsteadiness of gait, vomiting and extreme lethargy, some are already having seizures which if initially brought under control are put down to febrile seizures.
Some patients are diagnosed with Encephalitis or Meningitis if the symmetrical brain lesions are not recognised.
No genetic testing is done and this puts the patient and their family at risk of further attacks.
Our aim is for all Doctors to look a little deeper for neurological symptoms with a viral illness and be able to recognise the lesions specific to ANE on MRI.
That parents are aware of neurological symptoms and when to take action. Not only may this save the patients life but also other members in the family if ANE is genetic. Early treatment is crucial in slowing brain inflammation and hence damage.
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Fast Facts
*ANE can be both genetic and non genetic. Genetic cases are susceptible to recurrence.
*It is a severe & rapidly progressive acute disease.
*ANE is typically triggered by virus most commonly influenza. Other viruses include HSV6, varicella, rubella, measles, rotavirus, enterovirus and coxsackie 9. ANE on the rare occasion can be triggered by bacteria.
*It particularly affects previously well children.
*Typical viral symptoms (fever cough etc) rapidly progress to neurological signs including seizure & coma.
*Bi Lateral thalamic lesions are a distinctive feature on MRI
*Outcomes can include severe cognitive dysfunction, cerebral palsy, vision and speech issues.
*Mortality is high and almost all survivors are left with Acquired Brain Injury
*The exact pathogenesis is unknown.
*It is a highly under recognised Rare disease that is often misdiagnosed.
Influenza is typically thought of as a respiratory illness. It is so important for treating physicians to always be on the lookout for neurological complications during any given flu season. The following is from “Neurological Manifestations of Hospitalized Children with Influenza During the 2016—2017 Season,” and was published online in the Journal of Pediatric Infectious Diseases Society.
“Influenza viruses cause a variety of neurologic manifestations in children, including simple and complex febrile seizures, exacerbations of underlying seizure disorders, encephalopathy and encephalitis,” study authors wrote. “The type and frequency of influenza-associated neurologic diseases in children are influenced by circulating strains, predisposing host factors and uptake and efficiency of influenza vaccinations.”
In the study, investigators sought to identify clinical characteristics of children with neurological manifestations of influenza, as well as to compare demographics and clinical characteristics with influenza-positive controls.
The retrospective cohort study analyzed 182 children admitted to the Children’s Hospital Colorado with an influenza infection between Dec. 27, 2016, and April 12, 2017. According to the study, children with neurological manifestations of influenza accounted for 43% of all influenza-related hospital admissions during this time span, and over half, or 54%, of these patients needed ICU care.
Investigators found that 18% had neurological manifestations of influenza, including seizures and encephalopathy. Furthermore, 85% of these children were infected with the prevalent H3N2 influenza strain. The majority of patients experienced seizures only, according to the study. The remaining patients experienced encephalopathy only, or both seizures and encephalopathy.
Patients with neurological manifestations of influenza were 3.5 times more likely to have neurological comorbidity than those without neurological manifestations, as well as a to-fold increase in chances of hospitalization.
Investigators acknowledged that 30% of children with neurologic manifestations of influenza had an underlying neurologic condition. However, these patients did not have more severe symptoms or greater morbidity compared with children without neurologic conditions, according to the study.
“Our findings suggest that influenza testing among febrile children with altered mental status or seizures should be considered and highlight the importance of influenza vaccination among children with an underlying neurologic disorder,” authors wrote.
The CDC recommends annual influenza vaccinations for children ages 6 months and older and has concluded that vaccinations are an important initial step in combating the flu. During the 2016-2017 influenza season, private manufacturers distributed approximately 145.9 million doses of the influenza vaccination in the US.
The last 12 months has seen new interest in Acute Necrotizing Encephalopathy and also continuing studies & research.
We believe some of the gaps in the knowledge of ANE has been noted (in the medical community) in part due to the Covid-19 pandemic. We are seeing recognition of these gaps, particularly treatments and the lack thereof. With studies being done on the cytokine storm that occurs in some Covid patients we are very hopeful that this will transfer to be of benefit to ANE patients.
Currently our ANE community stands at 311 members with approximately 120 different families, some with multiple family members being genetic carriers and/or affected by ANE. We are also aware of many cases of ANE (news articles, case reports etc) that we have not been able to reach.
To this day patients are still told there are only 150-300 cases reported worldwide and of these around 59 genetic cases. This number is grossly underestimated and we would love to see a new collation of published ANE case reports completed. This year we shared an article from Egypt that had 30 ANE children admitted in 17 months at the one hospital (1).
Influenza numbers globally have been very low due to the various measures undertaken to limit the spread of Covid19. This however did not mean that our support group didn’t gain new members. Families that have only just found us or members with rarer or unknown triggers were welcomed.
#ANEawareness
Alexander Palazzo and his team at the Palazzo lab in Toronto, Canada continue to research Ranbp2 (where the most common genetic variations for ANE are found). Unfortunately due to the worldwide pandemic some of this work has had to be put on hold. We were greatly disappointed that a planned workshop where ANE families could attend and provide specimens for Alex’s research was also postponed. Various speakers on different aspects of ANE were to present at the workshop. This was also to be an opportunity for many families to meet for the first time, learn about ANE and contribute to research. However, it was wonderful to see new articles with some exciting work from Alex and his team published (2). We congratulate them and thank them for this achievement and for their many, many hours of work.
#ANEawareness
We are pleased to say that we have broadened our international contact base for physicians and researchers this year. They are either creating studies or research on different aspects of ANE or have expressed an interest in collaborating with us to further meet the needs and goals of ANE International as a Patient Advocacy Group focused on Education, Awareness and Support. We are excited for what the future may hold.
#ANEawareness
It came as no surprise to our community that Covid-19/ANE associated case reports were published in the relatively early days of the pandemic. What did surprise us was that these were in adults. To date, in comparison to overall pandemic numbers Covid 19/ANE appears to be very rare. There have been even less reports in children.
To date and to the best of our knowledge none of these reports have mentioned genetic testing in the patients. We feel that this was a real missed opportunity, not only for further knowledge for our families but for ANE as a whole.
We questioned why the term “Acute Hemorrhagic Necrotizing Encephalopathy” was often used in reports of some of these adult Covid cases. Acute Necrotizing Encephalopathy is listed as its own entity on the Genetic and Rare Disease (Gard) website (3) and Infection Induced Acute Encephalopathy 3, IIAE3 (genetic ANE) listed as a subtype.
Under IIAE3 are other names that ANE is known as; here we find postinfectious acute necrotizing hemorrhagic encephalopathy alongside ANEC, ADANE, ANE1 among others. As an organisation promoting awareness we find this quite frustrating that other less known labels are being used.
However, the further study of Covid19 associated ANE may reveal differences in the disease with this trigger and why it seems to particularly affect adults. From the article – COVID-19–associated acute necrotising encephalopathy successfully treated with steroids and polyvalent immunoglobulin with unusual IgG targeting the cerebral fibre network (yes…that is quite a mouthful!) (4) we find the following comment in conclusion.
COVID-19-mediated ANE with IgG antibodies emerging from peripheral tissues and targeting the cerebral fibre network around basal ganglia is a possible new entity that should be further studied.
The following reference from the article, Acute Necrotizing Encephalopathy: A Disease Meriting Greater Recognition (5) notes differences between adult and child cases.
Among the observed differences between ANE in adults and children, the authors report higher white matter (89%) and cerebellar (100%) involvement, in addition to parenchymal hemorrhage (90%), in adults. Our previous study of pediatric ANE found cerebellar lesions in only 23% of affected children. The reason for the higher occurrence rate in adults than children is not considered in detail by the authors, but it may reflect differences in infectious agents, genetic background, immune response, and age-specific tissue vulnerability.
It remains to be seen if further research can elucidate on Covid19 associated ANE and adult versus child cases.
#ANEawareness
To finish off we’d just like to say a huge thank you to all our ANE families. Our tribe. They are a truly wonderful group of people that even with cultural and language differences are always focused on lifting and supporting each other in so many different ways. They share their own lived experiences of ANE – the many types of grief, the milestones, joys and frustrations associated with such a devastating disease. Through all the unknowns that the pandemic has brought, the feeling of oneness, that we are not alone within our community is truly invaluable. To the many friends & family that support our members and the ANE community as a whole we thank you. We acknowledge the support of all who follow ANE International and continue to help us raise awareness. There are a whole lot of Us in #ANEandUs and for that we are truly grateful.
#ANEawareness
(1). Ibrahim, R.S.M., Elzayat, W., Seif, H.M. et al. Multi-parametric magnetic resonance imaging in acute necrotizing encephalopathy of children: validity and prognostic value. Egypt J Radiol Nucl Med51, 113 (2020). https://doi.org/10.1186/s43055-020-00214-1
(2) Qingtang Shen, Yifan E Wang, Alexander F Palazzo, et al Crosstalk between nucleocytoplasmic trafficking and the innate immune response to viral infection Journal of Biological Chemistry JBC Reviews/Articles in Press, 100856
Qingtang Shen, Yifan E. Wang, Mathew Truong, Kohila Mahadevan, Jingze J. Wu, Hui Zhang, Jiawei Li, Harrison W. Smith, Craig A. Smibert, Alexander F. Palazzo, et al RanBP2/Nup358 enhances miRNA activity by sumoylating Argonautes PLOS Genetics February 18, 2021
(4) Delamarre L, Gollion C, Grouteau G NeuroICU Research Group, et alCOVID-19–associated acute necrotising encephalopathy successfully treated with steroids and polyvalent immunoglobulin with unusual IgG targeting the cerebral fibre network Journal of Neurology, Neurosurgery & Psychiatry 2020;91:1004-1006.
(5) H Kikokoro, Acute Necrotizing Encephalopathy: A Disease Meriting Greater Recognition American Journal of Neuroradiology December 2020, 41 (12) 2255-2256;
Influenza is typically thought of as a respiratory illness. It is so important for treating physicians to always be on the lookout for neurological complications during any given flu season. The following is from “Neurological Manifestations of Hospitalized Children with Influenza During the 2016—2017 Season,” and was published online in the Journal of Pediatric Infectious Diseases Society.
“Influenza viruses cause a variety of neurologic manifestations in children, including simple and complex febrile seizures, exacerbations of underlying seizure disorders, encephalopathy and encephalitis,” study authors wrote. “The type and frequency of influenza-associated neurologic diseases in children are influenced by circulating strains, predisposing host factors and uptake and efficiency of influenza vaccinations.”
In the study, investigators sought to identify clinical characteristics of children with neurological manifestations of influenza, as well as to compare demographics and clinical characteristics with influenza-positive controls.
The retrospective cohort study analyzed 182 children admitted to the Children’s Hospital Colorado with an influenza infection between Dec. 27, 2016, and April 12, 2017. According to the study, children with neurological manifestations of influenza accounted for 43% of all influenza-related hospital admissions during this time span, and over half, or 54%, of these patients needed ICU care.
Investigators found that 18% had neurological manifestations of influenza, including seizures and encephalopathy. Furthermore, 85% of these children were infected with the prevalent H3N2 influenza strain. The majority of patients experienced seizures only, according to the study. The remaining patients experienced encephalopathy only, or both seizures and encephalopathy.
Patients with neurological manifestations of influenza were 3.5 times more likely to have neurological comorbidity than those without neurological manifestations, as well as a to-fold increase in chances of hospitalization.
Investigators acknowledged that 30% of children with neurologic manifestations of influenza had an underlying neurologic condition. However, these patients did not have more severe symptoms or greater morbidity compared with children without neurologic conditions, according to the study.
“Our findings suggest that influenza testing among febrile children with altered mental status or seizures should be considered and highlight the importance of influenza vaccination among children with an underlying neurologic disorder,” authors wrote.
The CDC recommends annual influenza vaccinations for children ages 6 months and older and has concluded that vaccinations are an important initial step in combating the flu. During the 2016-2017 influenza season, private manufacturers distributed approximately 145.9 million doses of the influenza vaccination in the US.
The last 12 months has seen new interest in Acute Necrotizing Encephalopathy and also continuing studies & research.
We believe some of the gaps in the knowledge of ANE has been noted (in the medical community) in part due to the Covid-19 pandemic. We are seeing recognition of these gaps, particularly treatments and the lack thereof. With studies being done on the cytokine storm that occurs in some Covid patients we are very hopeful that this will transfer to be of benefit to ANE patients.
Currently our ANE community stands at 311 members with approximately 120 different families, some with multiple family members being genetic carriers and/or affected by ANE. We are also aware of many cases of ANE (news articles, case reports etc) that we have not been able to reach.
To this day patients are still told there are only 150-300 cases reported worldwide and of these around 59 genetic cases. This number is grossly underestimated and we would love to see a new collation of published ANE case reports completed. This year we shared an article from Egypt that had 30 ANE children admitted in 17 months at the one hospital (1).
Influenza numbers globally have been very low due to the various measures undertaken to limit the spread of Covid19. This however did not mean that our support group didn’t gain new members. Families that have only just found us or members with rarer or unknown triggers were welcomed.
#ANEawareness
Alexander Palazzo and his team at the Palazzo lab in Toronto, Canada continue to research Ranbp2 (where the most common genetic variations for ANE are found). Unfortunately due to the worldwide pandemic some of this work has had to be put on hold. We were greatly disappointed that a planned workshop where ANE families could attend and provide specimens for Alex’s research was also postponed. Various speakers on different aspects of ANE were to present at the workshop. This was also to be an opportunity for many families to meet for the first time, learn about ANE and contribute to research. However, it was wonderful to see new articles with some exciting work from Alex and his team published (2). We congratulate them and thank them for this achievement and for their many, many hours of work.
#ANEawareness
We are pleased to say that we have broadened our international contact base for physicians and researchers this year. They are either creating studies or research on different aspects of ANE or have expressed an interest in collaborating with us to further meet the needs and goals of ANE International as a Patient Advocacy Group focused on Education, Awareness and Support. We are excited for what the future may hold.
#ANEawareness
It came as no surprise to our community that Covid-19/ANE associated case reports were published in the relatively early days of the pandemic. What did surprise us was that these were in adults. To date, in comparison to overall pandemic numbers Covid 19/ANE appears to be very rare. There have been even less reports in children.
To date and to the best of our knowledge none of these reports have mentioned genetic testing in the patients. We feel that this was a real missed opportunity, not only for further knowledge for our families but for ANE as a whole.
We questioned why the term “Acute Hemorrhagic Necrotizing Encephalopathy” was often used in reports of some of these adult Covid cases. Acute Necrotizing Encephalopathy is listed as its own entity on the Genetic and Rare Disease (Gard) website (3) and Infection Induced Acute Encephalopathy 3, IIAE3 (genetic ANE) listed as a subtype.
Under IIAE3 are other names that ANE is known as; here we find postinfectious acute necrotizing hemorrhagic encephalopathy alongside ANEC, ADANE, ANE1 among others. As an organisation promoting awareness we find this quite frustrating that other less known labels are being used.
However, the further study of Covid19 associated ANE may reveal differences in the disease with this trigger and why it seems to particularly affect adults. From the article – COVID-19–associated acute necrotising encephalopathy successfully treated with steroids and polyvalent immunoglobulin with unusual IgG targeting the cerebral fibre network (yes…that is quite a mouthful!) (4) we find the following comment in conclusion.
COVID-19-mediated ANE with IgG antibodies emerging from peripheral tissues and targeting the cerebral fibre network around basal ganglia is a possible new entity that should be further studied.
The following reference from the article, Acute Necrotizing Encephalopathy: A Disease Meriting Greater Recognition (5) notes differences between adult and child cases.
Among the observed differences between ANE in adults and children, the authors report higher white matter (89%) and cerebellar (100%) involvement, in addition to parenchymal hemorrhage (90%), in adults. Our previous study of pediatric ANE found cerebellar lesions in only 23% of affected children. The reason for the higher occurrence rate in adults than children is not considered in detail by the authors, but it may reflect differences in infectious agents, genetic background, immune response, and age-specific tissue vulnerability.
It remains to be seen if further research can elucidate on Covid19 associated ANE and adult versus child cases.
#ANEawareness
To finish off we’d just like to say a huge thank you to all our ANE families. Our tribe. They are a truly wonderful group of people that even with cultural and language differences are always focused on lifting and supporting each other in so many different ways. They share their own lived experiences of ANE – the many types of grief, the milestones, joys and frustrations associated with such a devastating disease. Through all the unknowns that the pandemic has brought, the feeling of oneness, that we are not alone within our community is truly invaluable. To the many friends & family that support our members and the ANE community as a whole we thank you. We acknowledge the support of all who follow ANE International and continue to help us raise awareness. There are a whole lot of Us in #ANEandUs and for that we are truly grateful.
#ANEawareness
(1). Ibrahim, R.S.M., Elzayat, W., Seif, H.M. et al. Multi-parametric magnetic resonance imaging in acute necrotizing encephalopathy of children: validity and prognostic value. Egypt J Radiol Nucl Med51, 113 (2020). https://doi.org/10.1186/s43055-020-00214-1
(2) Qingtang Shen, Yifan E Wang, Alexander F Palazzo, et al Crosstalk between nucleocytoplasmic trafficking and the innate immune response to viral infection Journal of Biological Chemistry JBC Reviews/Articles in Press, 100856
Qingtang Shen, Yifan E. Wang, Mathew Truong, Kohila Mahadevan, Jingze J. Wu, Hui Zhang, Jiawei Li, Harrison W. Smith, Craig A. Smibert, Alexander F. Palazzo, et al RanBP2/Nup358 enhances miRNA activity by sumoylating Argonautes PLOS Genetics February 18, 2021
(4) Delamarre L, Gollion C, Grouteau G NeuroICU Research Group, et alCOVID-19–associated acute necrotising encephalopathy successfully treated with steroids and polyvalent immunoglobulin with unusual IgG targeting the cerebral fibre network Journal of Neurology, Neurosurgery & Psychiatry 2020;91:1004-1006.
(5) H Kikokoro, Acute Necrotizing Encephalopathy: A Disease Meriting Greater Recognition American Journal of Neuroradiology December 2020, 41 (12) 2255-2256;
Forever in our hearts; all the warriors who have lost their battle with Acute Necrotizing Encephalopathy. When a loved one passes away, we keenly feel the need to express what they meant to us, ANE International honour’s their memory on this awareness day! FOREVER IN OUR HEARTS.
ANE International believes that now is the time to act, to provide hope and share knowledge to the general public, medical communities and ANE families who are impacted by acute necrotizing encephalopathy, a rare disease.For many rare diseases, basic knowledge such as the cause of the disease,pathophysiology, natural course of the disease and epidemiological data is limited or not available. This significantly hampers the ability to both diagnose and treat these diseases. To address this challenge, public funding of fundamental research into the disease process remains necessary both at the national and global level. Rare disease patients are scattered across countries. As a result, medical expertise for each of these diseases is a scarce resource. Fragmented disease knowledge means that it is critical that investments in fundamental research go hand-in-hand with investments in dedicated infrastructure and international networks (biobanks, registries, networks of expertise). Where needed, these networks can also provide opportunities to train health professionals on rare diseases.
Forever in our hearts; all the warriors who have lost their battle with Acute Necrotizing Encephalopathy. When a loved one passes away, we keenly feel the need to express what they meant to us, ANE International honour’s their memory on this awareness day! FOREVER IN OUR HEARTS.
ANE International believes that now is the time to act, to provide hope and share knowledge to the general public, medical communities and ANE families who are impacted by acute necrotizing encephalopathy, a rare disease.For many rare diseases, basic knowledge such as the cause of the disease,pathophysiology, natural course of the disease and epidemiological data is limited or not available. This significantly hampers the ability to both diagnose and treat these diseases. To address this challenge, public funding of fundamental research into the disease process remains necessary both at the national and global level. Rare disease patients are scattered across countries. As a result, medical expertise for each of these diseases is a scarce resource. Fragmented disease knowledge means that it is critical that investments in fundamental research go hand-in-hand with investments in dedicated infrastructure and international networks (biobanks, registries, networks of expertise). Where needed, these networks can also provide opportunities to train health professionals on rare diseases.
ANE International 