To improve comparability of vaccine safety data, the acute neonatal encephalopathy working group has developed a case definition and guidelines neonatal encephalopathy applicable in study settings with different availability of resources, in healthcare settings that differ by availability of and access to health care, and in different geographic regions.
The definition and guidelines were developed through group consensus. They are grounded on both expert opinion and a systematic literature review related to the assessment of acute neonatal encephalopathy as an adverse event following immunisation and to the diagnosis of acute neonatal encephalopathy in humans.
Encephalopathy is a general term used to define disease, malfunction or damage of the brain. The major symptom of encephalopathy is an altered mental state [1]. Defining altered mental state in the newborn is significantly more challenging than in the adult and there are no established direct measures to determine level of consciousness in the newborn. Nevertheless, specific clinical signs reflecting neurological function correlate with the overall severity of the encephalopathy. These clinical signs have been grouped in stages, usually three of them: mild, moderate and severe as in the Sarnat classification. The Sarnat criteria remain as the most commonly accepted classification [2], [3].
Neonatal encephalopathy has several potential etiologies and acute hypoxia-ischemia is the most studied cause. Over the years, the term “neonatal encephalopathy”, has been used by many as a synonym of “Hypoxic-ischemic encephalopathy”. The reason is that other etiologies are often reported as a specific diagnosis, as in the case of inborn errors of metabolism (e.g. non-ketotic hyperglycinemia), infections (e.g. meningitis) and other specific causes. It is therefore imperative to emphasize that many different processes leading to neonatal encephalopathy may develop prenatally, at birth or immediately post-delivery, and result from mainly, but not exclusively, genetic, metabolic, infectious, and traumatic processes. The common denominator in neonatal encephalopathy is the loss of homeostasis which can lead to abnormal brain function and potentially to brain structural changes [2], [3], [4].
Investigations such as magnetic resonance Imaging and neurophysiological technologies such as electroencephalography and evoked potentials are aids in exploring the severity and prognosis of neonatal encephalopathy, but are not required for its diagnosis. MRI brain can be reported normal in 15–30% of cases of confirmed mild cases (Sarnat 1) of hypoxic ischemic encephalopathy [1], [5].
The EEG is the most specific test to confirm and diagnose that a clinical paroxysm is epileptic in origin [9]. Electrographic pathological patterns correlate with neonatal seizures during seizure recording and subtle or subclinical seizures can often only be diagnosed by EEG monitoring. Once anti-seizure medications are administered, up to 58% of treated neonates exhibit electro-clinical uncoupling, in which the clinical signs of their seizures vanish despite the persistence of subclinical electrographic seizures [9].
EEG however has important technical limitations in the recording of some epileptic seizures, particularly those originating in mesial or midline areas of the brain. Also EEG is not always readily available for recording in the NICU. Amplitude integrated EEG (aEEG) is becoming widely used by neonatologists. This recording compresses the time scale of conventional EEG. It has lesser spatial resolution and is less sensitive for the detection of neonatal seizures compared to long term monitoring by conventional EEG [10], [11]. Abnormalities on the neonatal EEG such as discontinuity of the background or central sharp waves are not specific and will vary depending on external factors such as gestational age, body temperature during therapeutic cooling and medications [7].
Therefore, as per World Health Organization guidelines on neonatal seizures, the most practical method of diagnosis is the clinical recognition of neonatal seizures [8].
The Task Force on Neonatal Encephalopathy group on Neonatal Encephalopathy and Neurological outcome published in 2014 a comprehensive document defining Neonatal encephalopathy as “a clinical syndrome in an infant born at or beyond 35 weeks of gestation, manifested by a subnormal level of consciousness or seizures, and often accompanied by difficulty with initiating and maintaining respiration and depression of tone and reflexes” [5]. It was the consensus of our group to replace the word “consciousness” with the word “alertness” since the definition of “consciousness” is more vague. We also considered it necessary to include in the definition the concept of multiple potential etiologies.
