FIRES: First fever, then epilepsy

Febrile infection-related epilepsy syndrome is a devastating disease that rarely responds to aggressive therapies. A look at the literature shows that ketogenic diets can at least alleviate the suffering.

Around 500,000 patients in Germany suffer from epilepsy. A very rare variant, febrile infectious epilepsy syndrome (FIRES), affects one in one million children. The rare disease, which has been little researched so far, begins with an elevated temperature and culminates in long epileptic episodes. The risk of permanent damage is high. The disease is one of the most severe and dangerous forms of epilepsy worldwide.

One disease, many names

FIRES is a catastrophic epileptic encephalopathy with known febrile infection occurring at the onset of refractory Status epilepticus precedes. Signs of an identified infectious encephalitis are not available. for this entity different names including acute encephalitis with refractory repeated partial seizures (AERRPS), emerging refractory status epilepticus (NORSE), devastating epileptic encephalopathy in school-age children (DESC), febrile refractory epileptic encephalopathy in school-age children (FIRES), and febrile infectious epilepsy syndrome (FIRES).

The Kiel researcher Dr. Andreas van Baalen coined the term FIRES and continues to research the disease. In 2011 it was suggested that these conditions represent the same epileptic entities. Mechanisms of infection, inflammation-mediated processes, metabolic diseases, monogenic epilepsy genes, genetic predisposition and autoimmunity have been proposed as pathogenic mechanisms of FIRES. Hepatic impairment, rash and arrhythmia are common during hospitalization in the acute stage of the disease process observed.

2 out of 10 children are currently dying as a result of the disease. The other children suffer late injuries and in most cases are dependent on help for the rest of their lives.

Process in two phases

FIRES presents a biphasic presentation, with the acute phase beginning with seizure activity lasting 1-12 weeks. A chronic phase follows, characterized by refractory, multifocal seizures that are frequent every 2 to 4 weeks and may be persistent. the Treatment of FIRES is difficult and typically does not respond to antiepileptic drugs.

Patients’ clinical seizures are mainly focal seizures, with or without progression to bilateral seizures, and persist despite intensive treatment with multiple antiepileptic drugs, immunosuppressants, a ketogenic diet and/or Burst-Suppression-Koma recurring and refractory. the initial findings magnetic resonance imaging (MRI) of the brain are often normal.

The immune system is involved

According to van Baalens, FIRES is an immune, but not an autoimmune disease, in which high-dose GABAergic therapy and the early introduction of enteral or even parenteral ketogenic nutrition as the most promising treatment is to be seen.

The inclusion criteria of FIRES in one Study from Shyu were:

1. Acute onset of first attack 2 to 10 days after previous febrile illness in previously healthy children
2. frequent seizures progressing to refractory status epilepticus,
3. the absence of an identified pathogen in the cerebrospinal fluid,
4. prolonged acute phase of more than two weeks,
5. persistent fever during the acute phase of the disease and
6. continuous transition to refractory epilepsy without a latency period.

The study found that FIRES patients had varying degrees of liver dysfunction associated with reversible injuries Hepatomegaly or jaundice to irreversible liver failure. There was a rash or Stevens-Johnson-Syndrom. It has been observed that the occurrence and severity of skin rashes increases when multiple antiepileptic drugs are administered within a short period of time.

In addition, the acute stage were common Arrhythmias found. Two possible causes of arrhythmia have been observed. First, several drugs with side effects of arrhythmia, such as Phenytoin, Lidocaine and inotropic agents administered concomitantly. Second, FIRES itself induced seizure-induced neurogenic arrhythmia. The more frequent the seizures, the more obvious the arrhythmia was.

Which shows the largest case series to date

In the largest published so far Fall series with 77 children with the FIRES syndrome by Kramer et al. the following came about:

• About 1 in 10 children died as a result of status epilepticus or complications in the intensive care unit.
• Almost all surviving children have chronic epilepsy that requires medical treatment.
  1. Developmentally, 3 in 10 children had normal or borderline cognitive function (with or without behavioral problems).
  2. 3 out of 10 children had mild to moderate cognitive delay.
  3. 3 out of 10 children had a severe delay.

“No therapeutic agent was effective in shortening the acute phase, with the possible exception of a ketogenic diet,” the authors said.

Antiepileptic drugs often not effective

Systematic studies are lacking and the few published case series suggest several therapeutic approaches. In most cases, the children have to be placed in an artificial coma for days or even months due to the severity. Regarding the previously discussed role of inflammation in the pathogenesis of FIRES, high-dose intravenous steroids, despite the risk of serious adverse events, tries.

First-line treatment initially consists of benzodiazepines (Lorazepam, Diazepam, Midazolam, Clonazepam), followed by standard antiseizure drugs, although FIRES typically does not respond to high doses of conventional antiseizure drugs. In terms of treatment methods, high-dose Phenobarbital in the literature proven effective in FIRES patients. Enteral lorazepam can be an effective surrogate for weaning midazolam-dependent children with FIRES. Early introduction of enteral lorazepam was associated with reduced length of hospital stay, according to one Study.

Some case reports document the positive effect of intravenous immunoglobulin. isolated was used in patients who do not respond to antiepileptic drugs Anakinra used, a recombinant and modified version of the human interleukin-1 receptor antagonist protein. The drug is currently approved for the treatment of autoinflammatory diseases, including in newborns and children, and has potent anticonvulsant properties in animal models shown.

Ketogenic diet promising

In addition to conventional antiepileptic drugs, an early ketogenic diet could improve both seizure control and cognitive outcome according to FIRES optimize. It has been hypothesized that the ketogenic diet may not only have an anticonvulsant effect (e.g. through the production of n-decanoic acid, which induces a direct inhibition of postsynaptic excitatory AMPA), but also an anti-inflammatory one. This could be of great importance in the treatment of FIRES. Early introduction of a ketogenic diet could help not only during the acute phase but also in long-term epilepsy management be effective.

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The ketogenic diet has been used to treat children with refractory epilepsy since the 1920s. Also one intravenous form of the diet applies. A high ketogenic ratio (e.g. 4:1 of grams of fat to protein and carbohydrates) is aimed for, but a ratio of 1:1 is also feasible. Protein should be prioritized over carbohydrates, fluid and calories should be maximized, and a fat intake of 3 to 4 g/kg/day should be aimed for.

Urgently more work needed

FIRES is a devastating epilepsy syndrome. Despite aggressive medical treatments, the clinical results are disappointing. In the literature the acute-stage mortality rate ranged from 0% to 20%, residual/refractory epilepsy during long-term follow-up ranged from 83% to 100%, and severe mental retardation or vegetative state ranged from 28% to 38%. Studies on the underlying pathomechanisms of FIRES are urgently needed to develop new treatment strategies that may lead to improved long-term outcomes.

Image source: Tengyart, unsplash