Perspective asupra mecanismelor neurobiologice implicate în encefalopatia febrilă acută la copii

Introduction

Encephalopathy is a nonspecific term derived from Greek, meaning “disease of the brain”. It refers primarily to a clinical syndrome rather than a single disease, with diverse etiologies that may involve multiple organ systems beyond the central nervous system (CNS). A child presenting with fever, altered cognition or behavior, and changes in sensorium and/or seizures is classified as having acute febrile encephalopathy (AFE). Acute febrile encephalopathy represents a medical emergency, posing significant diagnostic and therapeutic challenges for the pediatrician⁽¹⁾. AFE was defined as the acute onset of fever accompanied by an altered state of consciousness and/or seizures. Cases with a prolonged illness before presentation, prior treatment at another facility, or underlying chronic systemic conditions such as neurodevelopmental delay, malignancy, or immunosuppressive therapy may be present, but were not considered defining features of AFE. Similarly, children with metabolic encephalopathy, electrolyte disturbances without cerebrospinal fluid abnormalities, evidence of demyelination on neuroimaging, intracranial space-occupying lesions, febrile seizures, endocrine-related encephalopathy, or stroke identified during subsequent investigations could also be observed. Still, these conditions did not meet the criteria for acute febrile encephalopathy.

Attention was given to any preceding symptoms such as upper respiratory tract infection, flu-like illness, or diarrhea, as well as potential exposures, including animal bites, recent vaccinations, contact with individuals with measles, chickenpox, or mumps, recent travel, or similar illnesses occurring in the neighborhood. Socioeconomic status was recognized as an important factor to consider. Clinical evaluation included vital signs, anthropometric measurements, a comprehensive physical examination and a detailed systemic assessment with particular focus on neurological status. Nutritional status was classified according to the Indian Academy of Pediatrics (IAP) guidelines⁽²⁾. The level of consciousness was determined using the modified Glasgow Coma Scale (GCS)⁽³⁾. Raised intracranial pressure was diagnosed when two or more of the following signs were present: elevated blood pressure, bradycardia, irregular respiration, abnormal tonic posturing, bulging or nonpulsatile anterior fontanel (if open), a positive “crackpot” sign, or papilledema on direct ophthalmoscopy (if the fontanel was closed)⁽⁴⁾. Remember that infants and severely ill children may not have meningeal signs despite a meningeal infection or inflammation.

Etiology

There are many possible etiologies in a child presenting with both fever and encephalopathy. Nevertheless, in tropical regions, infections of the central nervous system are the leading cause of febrile encephalopathy in the pediatric population. The spectrum of infectious agents varies significantly across different parts of the world, which also influences the choice of empirical treatment.

From a clinical standpoint, these conditions can be broadly classified into two groups:

• febrile encephalopathy with meningeal signs
• febrile encephalopathy without meningeal signs.

It is important to note that meningeal signs may be absent in certain cases, particularly in infants and in critically ill children, even when meningeal infection or inflammation is present.

To investigate a possible infectious etiology of altered consciousness, specific serological tests are recommen­ded to help identify the responsible pathogens.

• Lyme enzyme-linked immunosorbent assay (ELISA) – positive ELISA results should be confirmed by Western blot.
• Ehrlichia antibodies should be confirmed by indirect fluorescent antibody test (IFA).

To determine the etiology of febrile encephalopathy, a lumbar puncture is recommended, with cerebrospinal fluid analyzed using the tests presented in Table 3.

Neurobiology

Neuroinflammation and immune activation

Systemic or central nervous system infections trigger the release of proinflammatory cytokines such as interleukin-1b, interleukin-6 and tumor necrosis factor a. These mediators increase blood-brain barrier permeability, activate microglia and astrocytes, and promote cerebral edema, leading to impaired neuronal signaling.

Blood-brain barrier dysfunction

Inflammatory processes and hyperthermia compromise the integrity of the blood-brain barrier, facilitating the entry of toxins and inflammatory molecules into the brain parenchyma, thereby exacerbating neurotoxicity.

Metabolic stress and hypoxia

The developing brain has high metabolic demands. Fever, seizures, sepsis and hemodynamic instability may result in cerebral hypoxia and mitochondrial dysfunction, reduced ATP production and accumulation of lactate, all of which contributing to neuronal injury.

Glutamate-mediated excitotoxicity

Inflammation and hypoxia increase extracellular glutamate and impair its reuptake, causing excessive activation of NMDA and AMPA receptors, calcium influx and subsequent neuronal damage.

Microglial activation and axonal injury

Activated microglia release reactive oxygen species and proteolytic enzymes, which damage axons and myelin, contributing to persistent neurological deficits.

Vulnerability of the immature brain

In children, especially infants, incomplete neuronal maturation, limited antioxidant defenses and a relatively permeable blood-brain barrier increase the susceptibility to inflammatory and metabolic injury.

Electroencephalography (EEG)

Specific EEG findings can include epileptiform discharges indicative of complex partial status, triphasic waves associated with hepatic or uremic encephalopathy, and periodic lateralized epileptiform discharges suggestive of herpes encephalitis or other focal encephalitis⁽⁶⁾. More frequently, nonspecific patterns such as diffuse theta and delta activity, loss of faster frequencies and intermittent rhythmic delta activity are observed. Emerging evidence indicates that electrographic seizures may contribute to neuronal injury and adversely affect the outcomes. Many of these seizures are clinically silent, and may not be detected through routine observation, making continuous EEG (cEEG) monitoring essential for accurate identification. Therefore, when available, cEEG is recommended for all children presenting with acute encephalopathy⁽⁷⁾.

Brain MRI

Magnetic resonance imaging (MRI) is highly effective in assessing the extent and severity of both infectious and non-infectious brain disorders. Diffusion-weighted imaging (DWI) allows early detection of lesions in viral encephalitis and in patients with parenchymal complications following meningitis. MRI is also valuable in distinguishing pyogenic abscesses from other ring-enhancing lesions. It can reveal characteristic patterns, such as frontotemporal involvement in herpes simplex encephalitis, thalamic lesions in Japanese encephalitis, demyelinating changes in acute disseminated encephalomyelitis (ADEM) and necrotizing lesions in acute necrotizing encephalopathy⁽⁸⁾. Compared with CT, magnetic resonance imaging is more sensitive for identifying early changes of herpes encephalitis, which may appear within the first 48 hours on T2-weighted or FLAIR sequences⁽⁹⁾. In enterovirus 71 (EV71) encephalitis, MRI typically demonstrates T2 hyperintense lesions in the brainstem and cerebellar dentate nuclei. MRI can also provide diagnostic clues for less common infections, including those involving cryptococcal, fungal, or amoebic infections of the brain⁽¹⁰⁾. The extent of abnormalities observed on MRI may also help predict clinical outcomes. In addition, proton magnetic resonance spectroscopy (MRS) can reveal specific metabolite patterns, such as lactate and cytosolic amino acids, which are indicative of abscess formation.

Conclusions

Acute febrile encephalopathy in children represents a serious and multifaceted neurological condition, arising from the complex interaction between infection, systemic inflammation and the intrinsic vulnerability of the developing brain. Current evidence indicates that neuroinflammatory cascades, blood-brain barrier disruption, metabolic failure, excitotoxic neuronal injury and microglial activation are central to the pathogenesis of this syndrome. The immature nervous system exhibits heightened susceptibility to cytokine-mediated damage and oxidative stress, which partly explains the greater severity and variability of clinical outcomes in the pediatric population compared with adults. These mechanisms do not act in isolation but rather potentiate one another, ultimately leading to diffuse cerebral dysfunction and, in some cases, to irreversible structural and neurocognitive sequelae.

A deeper understanding of these neurobiological pathways is crucial for enhancing early recognition, informing targeted therapeutic strategies and for developing neuroprotective interventions. Future research should focus on identifying reliable biomarkers, elucidating age-specific pathophysiological differences and optimizing timely, mechanism-based treatment approaches to reduce morbidity and long-term disability associated with acute febrile encephalopathy in children.

Autor corespondent:  Bogdan-Marius Istrate E-mail: istratem.bogdan@yahoo.com

CONFLICT OF INTEREST: none declared.

FINANCIAL SUPPORT: none declared.

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