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Acute Necrotizing Encephalopathy

Synonymes: ANE; infection-induced acute encephalopathy 3 or IIAE3, Acute Necrotizing Encephalopathy of Childhood; ANEC

Acute Necrotizing Encephalopathy (ANE) or Acute Necrotizing Encephalopathy of Childhood (ANEC) is a rare, severe and rapidly progressing encephalopathy (disease affecting the brain) which develops shortly after a viral infection. It is now known by its symmetrical lesions predominately in the bi lateral thalami, midbrain and/or hindbrain. ANE usually affects children, although teenage & adult cases have also been reported. Initially, it was thought to appear only in patients of Asian descent; however, worldwide cases have now been reported. (reference: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5329764/?tool=pmcentrez )

The name “acute necrotizing encephalitis” (ANE), as coined by van Bogaert, Radermecker, and Devos1 in 1955,  was originally used to designate a form of meningoencephalitis characterized by softening of the temporal lobes and related rhinencephalic structures, and microscopically by an extensive necrosis of these areas. (reference: https://www.researchgate.net/publication/271147871_Acute_Necrotizing_Encephalitis )

The incidence rate is unknown. There’s 250-300 reported case worldwide. The disease affects males and females almost equally. The mortality rate may be as high as 30%; however, full recovery is seen in about 10% of cases. (reference: https://ghr.nlm.nih.gov/condition/acute-necrotizing-encephalopathy-type-1 )

Acute necrotizing encephalopathy typically appears in infancy or early childhood, although some people do not develop the condition until adolescence or adulthood. People with this condition usually show typical symptoms of an infection, such as fever, cough, congestion, vomiting, and diarrhea, for a few days. Following these flu-like symptoms, affected individuals develop neurological problems, such as seizures, hallucinations, difficulty coordinating movements (ataxia), or abnormal muscle tone. Eventually, most affected individuals go into a coma, which usually lasts for a number of weeks. The condition is described as "acute" because the episodes of illness are time-limited. (reference: https://ghr.nlm.nih.gov/condition/acute-necrotizing-encephalopathy-type-1 ), The exact mechanism of the disease is not yet known. It is presumed to be an immune-mediated process triggered by the viral infection. In other words, people with ANE often may have an exaggerated immune response to various infections. ANE is not considered to be an inflammatory encephalitis as there are no signs of infection in the CSF or the brain (as seen in autopsies, when performed).

Causes:

Bacterial infections and viral infections are thought to induce ANE include influenza virus,  enterovirus, measles] mumps, rubella, varicella zoster, Human Herpesvirus 6 (HHV-6),  herpes simplex virus, hepatitis A, and coxsackievirus;

Diagnosis

Brain scans (Computed Tomography – CT and Magnetic Resonance Imaging-MRI) show symmetric multifocal lesions affecting the brain (thalami, brainstem, periventricular white matter and cerebellum are the most common although other areas may be affected). The bilateral thalamic lesions are a distinctive feature of ANE. The spinal cord is rarely involved.

Cerebrospinal fluid (CSF) testing shows elevated protein, but very rarely pleocytosis (increased cell count). Sometimes, pathogens (viruses) responsible for infection are found in the CSF.

Diagnosis is made based on the presence of viral infection before the development of ANE, signs of rapidly neurological deterioration, the results of the brain scans (specifically the symmetric multifocal lesions) and CSF testing and exclusion of resembling diseases.

(reference:www.aneinternational.org)

Treatment

There are no set guidelines for treating ANE. Treatment usually includes:

intensive care to help the patient perform their usual bodily functions (breathing machine, tubes and drips), high-dose steroids in viral infections, antiviral medications, symptomatic treatment (e.g. antiepileptic and/or seizure drugs), immunotherapies (e.g. IV glucocorticoids, immunoglobulin, and plasmapheresis),therapeutic hypothermia (reduction of the body temperature done on purpose). (reference: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2495887/pdf/postmedj00318-0053.pdf )

Recurrence and Familial Cases:

Most cases of ANE are isolated events and do not happen again. However, in some patients, the illness can re-occur and/or it can present itself in other family members. This type of ANE is called ANE1 or Infection-Induced Acute Encephalopathy-3 (IIAE3). It has been linked with mutations in the RANBP2 gene. The mutation of this gene has been detected in 75% of ANE family cases. However, the mutation in this gene is a risk factor in the occurrence of the disease and doesn’t imply that all individuals affected will develop ANE1. Half of them will suffer from ANE1 and half will be asymptomatic carriers. Additional genetic and environmental factors (viral infection) are also required for the disease to develop.

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Prognosis

The clinical course and the prognosis vary from patient to patient, ranging from a mild form with complete recovery (10%) to a severe form with a high mortality (30%). Due to the acquired brain injury, most of the survivors are left with neurological sequelae (e.g. motor deficits, epilepsy, developmental delay). Poor prognosis is associated with delayed diagnosis, involvement of brainstem (part of the brain that connects the brain with the spinal cord and controls the heart and lung functions) and recurrent episodes. Recurrent or familial ANE without the RANBP2 mutation has a more severe outcome and greater predilection for males than that with the RANBP2 mutation. This suggests that there are unknown gene mutations linked to ANE. (reference: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4115067/ )

RANBP2 Mutation:

It is becoming more common to have ANE patients and their families tested for a gene mutation. It is important to note, however, that even with the gene mutation, not all mutations will result in ANE. The actual trigger has yet to be determined. Probability of recurrence after the first episode, is 50% on trigger activation (ie. Influenza; HSV) and then 25% after a second episode. Note that triggers vary from one patient to the next. Some patients will only have 1 trigger while others will have multiple.

At least three mutations in the RANBP2 gene have been found to increase the risk of developing acute necrotizing encephalopathy type 1 (ANE1). These mutations change single protein building blocks (amino acids) in the gene’s protein resulting in the production of a protein that cannot function properly. The mutations do not cause health issues on their own; it is not clear how they are involved in the process of a viral infection triggering neurological damage. (Reference:  https://ghr.nlm.nih.gov/gene/RANBP2#conditions )

HLA Genotypes (In Japanese Patients)

Whilst the mutation of the RANBP2 gene has been confirmed to be associated with ANE, the involvement of HLA genotypes has not at this point. However, a recent study confirms the likelihood. ANE has been reported worldwide, but this disease is reported predominantly in children living in East Asian countries. The difference in occurrence among various ethnic groups suggests the involvement of host genetic factors in ANE. Using 31 Japanese confirmed ANE patients a study was conducted in Japan and aimed for the first time to investigate genetic background of ANE within this ethnic group. Human leukocyte antigen (HLA) genotypes include HLA class I (HLA-A, -C and -B) and class II (HLA-DR, -DQ and -DP). These molecules play an important role in the immune response. The study focused on HLA genotypes as a predisposing factor to ANE since the abnormal innate immune reaction was provoked by a preceding infection. In addition, HLA have been reported to be associated with various diseases susceptibility, such as autoimmune diseases and infectious diseases.

After the study there was enough evidence to support the above but due to the rarity of ANE the availability of statistics was limited. Further similar studies are required to confirm these findings. The data from this study suggests that specific HLA Genotypes are involved in the manner of development of ANE. (reference: http://www.nature.com/gene/journal/v17/n6/full/gene201632a.html )

Other sources of information:

http://jamanetwork.com/journals/jamaneurology/article-abstract/563639

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1496871/

http://dx.doi.org/10.1155/2015/79257

https://www.ncbi.nlm.nih.gov/pubmed/27882739

http://www.mayoclinic.org/autosomal-dominant-inheritance-pattern/img-20006210

http://www.ncbi.nlm.nih.gov/books/NBK258641/

https://ghr.nlm.nih.gov/gene/RANBP2#conditions

http://www.brainline.org/content/2008/07/behavioral-considerations-associated-traumatic-brain-injury.htm