Paroxysmal events are common in the neonate. It is not always easy to tell if these episodes are epileptic seizures because ERG discharges may not always be seen in epileptic seizures at this age.

Non-epileptic events

Benign neonatal sleep myoclonus

If the physician is not able to observe an episode of this common condition then video recording is the only necessary investigation. If home videocamera or mobile phone filming is not possible, then the parents may be shown video recordings of known examples to confirm, "That's it."

Flurries of multiple flexion jerks in long runs are seen in sleep. EEG is not indicated but if ictal EEG is carried out it is most important to avoid misinterpreting rhythmic artefacts as epileptic discharges. Bear in mind that as with other non-epileptic events benign neonatal sleep myoclonus may be seen in newborn infants who are not entirely 'normal', and is common in neonatal abstinence syndrome.

Hyperekplexia

In a neonate with some combination of tremulousness, stiffness, and cyanotic attacks (with high voltage runs of EMG 'artefact' on ictal EEG and ECG traces  and with head retraction on tapping the tip of the nose and auditory startle, then UNA for analysis in a specialized laboratory is indicated.

Most cases are due to mutations in the gene for the alpha subunit of the strychnine-sensitive glycine receptor (GLRM1) or in that for GIyT2, the postsynaptic glycine transporter (SLC6A5).

Paroxysmal extreme pain disorder

Video recording of the paroxysmal autonomic manifestations, in particular the Harlequin sign, may be helpful to share with others experienced in this disorder. .SCN9A mutations may be analysed in a specialized laboratory.

Seizures (of presumed epileptic mechanism)

Initial investigations by a neonatologist will depend upon the clinical scenario. Cranial ultrasound will detect gross structural lesions. MRI will detect more, including the acute cerebral ischaemia (arterial or venous) most easily seen with diffusion-weighted imaging (DWT). When a cause is not thereby apparent then further investigations will be necessary, often simultaneously performed. What we say below refers to difficult, refractory, unexplained seizures of epileptic type.

Early investigations for rare treatable disorders

( Also see   Investigations in rare treatable disorders  )

Pyridoxal phosphate trial

Cessation of seizures will indicate either pyridoxal phosphate responsiveness or pyridoxine-dependent epilepsy. Confirmation of pyridoxine-dependent epilepsy will be bv finding α-AASA in blood and urine, followed by mutation analysis of the ALDH7A1 (antiquitin) gene. In pyridoxal-5'-phosphate-responsive seizures due to pyridox(am)ine phosphate oxidase (PNPO) deficiency there may be elevated threonine and glycine in plasma and CSF (and possibly reduced CSF homovanillic acid and 5-hydroxyindole acetic acid). CSF pyridoxal-5'-phosphate will also be reduced. Confirmation is by mutation analysis of the PNPO gene.

GLUT1 (glucose transporter 1) deficiency

To recognize GLUT1 deficiency investigations should be carried out just before a feed is due. Blood is best taken for glucose estimation immediately before CSF glucose is measured. In the absence of infection or haemorrhage, a CSF/plasma glucose ratio is strongly suggestive of a Glut1 deficiency. This diagnosis can be confirmed by specific mutation analysis or erythrocyte uptake studies.

Cerebral creatine disorders

An absent creatine peak on H-MRS is diagnostic of a creatine deficiency syndrome such as GAMT or AGAT deficiency. (H-MRS may also show increased glycine in glycine encephalopathy and increased lactate in mitochondrial disorders, but therapeutic options in these disorders are limited.)

Serine biosynthesis disorders

Disorders of each of the enzymes involved in the serine biosynthesis pathway have been described of which phosphoserine amino transferase deficiency might be the most potentially treatable. The essential investigation is estimation of the CSF serine and glycine level, after such fasting as can be tolerated (before a feed).

Investigations for less obvious diagnoses

A number of investigations may be done in parallel when common conditions have been dealt with and rare treatable disorders eliminated.

Electroencephalography

A normal-for-gestational-age interictal EEG is of little help in diagnosis, and various abnormalities are also nonspecific. Beyond early preterm birth and in the absence of severe asphyxia, a suppression-burst pattern (in which a 'flat' or isoelectric trace is interrupted by brief high-voltage discharges) suggests the following:

Glycine encephalopathy

Pyridoxine-dependent or pyridoxal phosphate-responsive epilepsy

Ohtahara syndrome' (inverted commas indicate that an underlying primary diagnosis should still be sought).

Table below summarizes the various known associations of neonatal suppresson-burst EEG

Brain imaging

Although many structural malformations, especially cortical dysplasia, are epileptogenic, the finding of structural abnormality on brain imaging does not exclude a metabolic explanation for neonatal seizures.

The following imaging features may be clues to metabolic disorders.

Basal ganglia/thalamic lesions:mitochondrial disorders, creatine synthesis defects.

Cystic encephalomalacia or localized infarction: sulphite oxidase deficiency, mitochondrial disorder.

Cerebellar or pontocerebellar hypoplasia: congenital defect of glycosylation/mitochondrial disorder.

Cortical dysplasia/neuronal heterotopia: peroxisomopathies, mitochondrial disorders, molybdenum cofactor deficiency.

White matter abnormalities: peroxisomal and mitochondrial disorders, organic acidaemias, aminoacidopathies.

Agenesis of the corpus callosum: many metabolic disorders, including glycine encephalopathy, pyruvate dehydrogenase and pyruvate decarboxylase deficiency, early-onset mitochondrial OXPHOS (oxidative phosphorylation) disorders.

Pericerbral or subdural collections: glutaric aciduria type 1, Menkes disease.

Brain H-MRSI

If possible this should be done at the same time as MRI to aid detection of some of the metabolic disorders listed above.

 Glycine encephalopathy

Particularly in the context of suppression-burst EEG blood and CSF glycine are measured simultaneously. In glycine encephalopathy the CSF: plasma glycine ratio is >0.1 (normal <0.025).

Mitochondrial disorder

Elevation of blood or CSF lactate or the finding of a lactate peak on H-MRS strongly point to a mitochondrial disorder and will lead to specialized mitochondrial studies

Peroxisomal disorders

A clinical phenotype with multisystem involvement plus nonspecific findings of disturbed liver function or calcific stippling on radiography may point to a peroxisomal disorder and measurement of very long chain fatty acids and other peroxisomal markets ( Also see Investigating peroxisomal disorders )

Congenital defect of glycosylation (CDG)

Multisystem involvement, nonspecific abnormalities of liver function, creatine kinase, etc. will prompt measurement of sialotransferrin.

Molybdenum cofactor deficiency - isolated sulphite oxidase deficiency

Multicystic encephalomalacia on imaging with or without other brain malformation will prompt estimation of uric acid (low in molybdenum cofactor deficiency) and total plasma homocysteine (low in isolated sulphite oxidase deficiency). For the urine sulphite test to have a chance of being positive the sample must be tested immediately, but true false negatives (and false postives) have been reported, so specific analysis of uric acid and total plasma homocysteine are mandatory.

Genetic studies

Chromosomal studies

Karyotyping would have been carried out in any undiagnosed neurological disorder. Various ring chromosome abnormalities should be sought in unexplained refractory seizures. Special tests for lp36 (see Chapter 2.13) are worth pursuing.

Single gene targeted investigations

Although it may not have a major impact on management, the detection of mutations or submicroscopic deletions or duplications or one of the epilepsy genes may be helpful to families. Such genes include KCNQ2 in benign familial neonatal seizures and SCN2A In benign neonatal infantile seizures.

Collagen gene mutations in apparent traumatic brain damage

The presence of perinatal cerebral haemorrhage ± porencephaly may reflect pathogenic mutations in the collagen 4 alpha-1 gene (COL4A1). Brain MRI of a parent may show leukoencephalopathy and/or silent microhaemorrhages (need echo-gradient sequence for detection); fundoscopic examination may reveal retinal arteriolar tortuosity.

Source:
Mary D. King, 2009. A Handbook of Neurological Investigations in Children. 1 Edition. Mac Keith Press.