Parent & Caregiver’s Guide to Acute Necrotizing Encephalopathy

Parents of a child newly diagnosed with Acute Necrotizing Encephalopathy (ANE) struggle comprehending the complex medical information being presented to them and the devastating implications of this diagnosis. We hope the information in this article will serve as an initial guide for families who are beginning their journey with ANE.

Recognising ANE

ANE is a rare type of brain disease (encephalopathy) that occurs following a viral infection such as the flu, and can sometimes be fatal. Children with ANE will start out with innocuous symptoms of a common febrile illness like Influenza – usually fever, cough and runny nose — or vomiting and diarrhoea, and then experience a deterioration in alertness and activity (an altered mental state). This deterioration is often what alerts the physician to the likelihood of ANE. In children with severe ANE, seizures may occur and there may be a rapid progression to a comatose state within 24–72 hours from the onset of symptoms.

Brain imaging plays an important role in diagnosis as there is a recognisable pattern of swelling (lesions) involving certain brain regions – typically in an area called the thalamus and in the brainstem. Some children have a variable elevation in liver enzymes, inflammatory markers such as C-reactive protein, and an elevation in the protein content of cerebrospinal fluid (CSF).

The febrile illness preceding ANE is usually caused by the influenza, herpes simplex, coxsackie and entero- viruses, but how these viruses induce ANE is not clear. It is postulated that the infection triggers an overreaction of the body’s immune system, called a ‘cytokine storm’. This reaction spills over into the brain, leading to brain oedema (swelling), haemorrhage (bleeding) and brain injury.

Genetics and Susceptibility

In most children, ANE is a random event. There is no inherent susceptibility and the ANE illness does not recur.  However, in some children recurrent episodes of ANE occur due to an inherited genetic predisposition. The most common gene attributed to inherit ANE is called RANBP2, a gene involved in energy metabolism in brain cells.

This genetic form of ANE is referred to as ANE1 and may be inherited from a parent (an “autosomal dominant” gene) or occur as a new genetic mutation in children with no prior family history of ANE.

It is important to know that not all children or family members carrying a RANBP2 genetic mutation will develop ANE. However, those who do develop ANE have a 50% risk of developing a recurrent episode of ANE. 

Treatment and Interventions in the acute phase of the ANE illness

Children with mild ANE may only need treatments for the febrile illness and concurrent respiratory or gastrointestinal tract infection and no specific therapies to address the brain condition. Children with severe ANE, however, deteriorate rapidly in the first days of the febrile illness and need admission to the intensive care unit (ICU) at the hospital. At the ICU, they require interventions to control breathing function through mechanical ventilation, administration of intravenous fluids and medications to support heart function and blood pressure. This will help ensure an adequate supply of oxygen and nutrients to swollen and injured brain regions which need to increase metabolism to weather the illness and limit the extent of brain injury. They may be placed in a medical coma, which entails administering sedative medication to quieten brain activity and allow the child to rest completely. Persistent seizures need to be treated promptly. 

In some children (usually non-genetic ANE), the condition may also cause the heart, liver and kidneys to fail. Hence, interventions to support the functions of these organs may be required. Some may develop a bleeding tendency and require an infusion of blood products.

Some common treatments are described in more detail on  our Treatment Page (click here). An important strategy is using medications to dampen the escalated immune response or cytokine storm observed in ANE with the use of corticosteroids or immunoglobulins. Newer approaches being explored are methods to tackle the cytokine storm more directly with therapeutic hypothermia or brain cooling therapy, which involves safely lowering the body and brain temperature, and using an interleukin-6 receptor antibody, a medication that specifically targets a cytokine responsible for inducing ANE.

The ANE Severity Score (ANE-SS) is a useful clinical tool that helps define disease severity and aids the prediction of outcome. Children stratified as having severe disease on the ANE-SS have a high risk of death and disability. This scoring tool also helps guide doctors to choose the most appropriate treatments and children who are most ill will generally receive more medications. The strategy employed or specific therapy agent chosen is best made in discussion with the clinical team managing your child as not all treatments are available in all hospitals and some treatments may be contraindicated in certain situations. Whichever approach is chosen, the early introduction of brain-directed treatments is most beneficial.

The journey after ICU and hospital 

Once children are over the sickest period and stable enough to be out of intensive care, they will have to undergo a period of rehabilitation. This would be no different from any acquired brain injury and will be delivered by a multidisciplinary team comprising of therapist, dietician (nutritionist) and rehabilitation physicians. Here the teams will evaluate the improvement potential and often provide families with some guidance as to the significant involvement and potential for recovery.

The recovery following an episode of ANE is very varied with some making a near full neurological recovery and some children left with profound disability. Whilst no two patients are the same, the extent of damage can be inferred from the brain scan alongside a careful evaluation of improvement over a period of time. Most recovery will begin to happen months after the event. 

An important management for ANE is early diagnosis of the genetic form which has a higher recurrence risk. In this form also commonly called ANE1 in the medical literature, the management should be driven by two important mainstay strategies. Firstly and crucially, is the early recognition of symptoms and seeking medical help. Earlier initiation of immune treatments are deemed important to avoid further progression of the relapse process. Because each relapse is so varied, this can be very difficult to have more definitive evidence but makes common medical sense. Secondly, management should be targeted at avoiding infections that are known to be associated with a poorer outcome, particularly influenza. In our 6 patients we currently care for with ANE, of whom 4 with ANE1 who had 13 acute events, confirmed influenza infections (4/13) resulted a much poorer recovery including 2 deaths. Influenza vaccination must be advocated in this group of patients.

 Future Research

 There is so much more we need to know about ANE. Why do infections trigger such a response? How does the gene defect contribute further to this process? By understanding these we can start to see how we can actually treat this condition better. Currently, doctors are starting to explore early use of anti-inflammatory agents and we need to study this effect more systematically to see if this is effective. As cases are rare, it is teams getting together and sharing real world clinical experience that will further our knowledge on this devastating condition.

Drs Sonia Khamis and Ming Lim are Paediatric Neurologists at Evelina Children’s Hospital in London, United Kingdom whilst Dr Terrence Thomas is a Paediatric Neurologist at KK Women’s and Children’s Hospital in SIngapore.