The symptoms may start appearing as early as a few hours after birth and up to three months of age. Around three-fourths of affected children present with neonatal seizure. Other seizure types such as focal or generalized tonic seizures, epileptic  spasms or other epileptic manifestations may occur at the course of the disease. The distinctive feature of the phenotype is severe progressive encephalopathy with delay in development and abnormal neurological examination delay (hypotonia, lethargy, poor eye contact, difficulties in feeding) usually being present even before the onset of other symptoms. Head circumference is usually normal at onset but microcephaly may develop over time. Family history is usually normal. Causes
There are varied etiologies related to EME that are mainly genetic abnormalities (mutations), brain structure abnormalities, or inborn metabolic defects. Another common reason rather than structural brain abnormality is inborn metabolic defects. Sometimes a metabolic disorder that affects how the brain works may lead to EME. While most of these metabolic disorders cannot be reversed, sometimes treating the underlying disorder can help. Vitamin-responsive epileptic encephalopathies are rare but significant reasons. Genetics
A growing number of genetic aetiologies have been linked to the phenotype of EME and Otahara syndrome and diagnosis by genetic testing can nowadays be achieved in around 50 percent of cases. Some examples of well described genetic aetiologies include: KCNQ2- DEE. • SCN2A-DEE • STXBP1-DEE. • CDKL5-DEE• KCNT1-DEE and UBA5-DEE. Acquired
No acquired aetiologies are known for EME although etiology remains unknown for a small percentage of patients after genetic, metabolic, and imaging workup.
Hyperalgesia ( or ; hyper from  Greek ὑπέρ (huper, “over”), -algesia from Greek  algos, ἄλγος (pain)) is an abnormally increased sensitivity to   pain, which may be caused by damage to nociceptors or peripheral nerves and can cause hypersensitivity to stimulus. Prostaglandins E and F are largely responsible for sensitizing the nociceptors. Temporary increased sensitivity to pain also occurs as part of sickness behavior, the evolved response to infection. Types
Hyperalgesia can be experienced in focal, discrete areas, or as a more diffuse, body-wide form. Conditioning studies have established that it is possible to experience a learned hyperalgesia of the latter, diffuse form. The focal form is typically associated with injury, and is divided into two subtypes:

Primary hyperalgesia describes pain sensitivity that occurs directly in the damaged tissues. Secondary hyperalgesia describes pain sensitivity that occurs in surrounding undamaged tissues.Opioid-induced hyperalgesia may develop as a result of long-term opioid use in the treatment of chronic pain. Various studies of humans and animals have demonstrated that primary or secondary hyperalgesia can develop in response to both chronic and acute exposure to opioids. This side effect can be severe enough to warrant discontinuation of opioid treatment. Causes
Hyperalgesia is induced by platelet-activating factor (PAF) which comes about in an inflammatory or an allergic response. This seems to occur via immune cells interacting with the peripheral nervous system and releasing pain-producing chemicals (cytokines and chemokines).One unusual cause of focal hyperalgesia is platypus venom.Long-term opioid (e.g.