Neonatal Seizures- Etiology, Clinical Features And Management

Epidemiology Of Neonatal Seizures

10.3 NNPD per 1000 lives. The relationship between birth weight and gestational age is inverse. Neonatal seizures are twice as likely to occur in preterm children. There is a 20% overall death rate; children with extremely low birth weights are four times more likely to experience newborn convulsions. Thirty percent will experience long-term neurological damage.

Why Are Seizures Very Common In Neonates?

Delayed maturation or development of newborn Na-K-ATPase. A higher N-methyl-D-aspartate receptor density. A higher density of AMPA receptors, particularly the Ca+2 influx-prone GLUR2 variety. A protracted GABAergic transmission development period.

Old concept

• In neonates, GABA is excitatory.
• In older children, GABA is inhibitory.

New concept

There is a lag between the development of excitatory and inhibitory transmission.

Also Read: High-Yield Image Based Questions On Neonatology

Types Of Neonatal Seizures

1. Subtle: Most common type of neonatal seizure.
2. Tonic
3. Clonic: Focal clinics are the second most common type of seizure.
4. Spasms
5. Myoclonic

Generalized tonic-clonic seizures are never seen in neonates.

Epileptic or Non-Epileptic

Electric activity on the EEG is linked to epileptic scissors. There is no discernible or absent comparable electric activity on the EEG during non-epileptic seizures. Generalized myoclonic focal tonic, focal clinic, and focal spasm epilepsy. Non-epileptics: Multifocal myoclonic, subtle, generalized tonic.

Subtle Seizures

Of all the types of newborn seizures, 50% are of the most frequent type.
There is more to preterms than terminology. Morphology: a brief deviation of the eyes, Nystagmus, fast blinking, mouthing, buccal-lingual motions, and aberrant motor movements. Examples include rowing, cycling, changes in blood pressure, pulse rate, and apnea episodes.  It may occur naturally or may be triggered by stimuli. Typically non-epileptic, as the EEG shows no electrical activity. In cases where apnea is present together with seizures, tachycardia or a normal heart rate will occur in relation to the apneic episodes. 

Clonic seizures 

There are rapid and slow components to the rhythmic, repeating 1 to 3 hertz motions of a set of muscles.

Categories 

Focal clonic; unifocal; multifocal (no Jacksonian movement); generalized clonic; these are extremely uncommon or nonexistent in neonates.

Tonic seizures

A set of muscles contracts continuously; these contractions might be localized or widespread.  Focal clonic: Asymmetrical limb or trunk posture that persists; typically associated with epilepsy.  Generalized tonic: Usually non-epileptic, bilaterally symmetrical, with the ability to flex the upper limb and extend the lower leg.  Generalized tonic > focused tonic in newborns

Spasm

Spasms can be flexor, extensor, or mixed clusters that cause abrupt, widespread jerks that last one to two seconds.  On an EEG, epilepsy is typically linked to electric discharge.  Their shorter duration and the fact that spasms are typically accompanied by a single, extremely brief, generalized discharge set them apart from generalized tonic scissors. 

Myoclonic

No sluggish component; rapid jerks (less than 50 msec) and non-rhythmic.  There are other subtypes of myoclonic seizures, such as focal myoclonic seizures, which typically involve the flexor muscles in the upper limb and exhibit epileptic activity.  Multifocal myoclonic: These cause no electrical activity on the EEG but impact several bodily muscles.  Generalized myoclonic seizures: They are bilaterally symmetrical and exhibit epileptic activity when they are connected to flexion of the lower limbs.

Jitteriness Versus Seizure

Tremulousness (tremors) in the limbs or orofacial region is known as jitteriness. Typically, a stimulus causes jitteriness.  Idiopathic or metabolic factors may be the cause of jitteriness. Hypoglycemia or hypocalcemia are examples of metabolic causes. A jittery person is sensitive to stimuli.

Also Read: Retinopathy of Prematurity- Mechanism and Treatment

Q. What Is Electroclinical Dissociation or Uncoupling ?

 The majority of these patients are discovered to have underlying encephalopathy, however their relevance is unknown;  Whenever there is seizure activity on the EEG but no real clinical seizure.  The likelihood of uncoupling is generally associated with unfavorable long-term neurological effects.

Benign Neonatal Sleep Myoclonus

In newborns, it is the most frequently misinterpreted condition as a seizure.  A neonate is said to be flourishing and healthy.  Possibly present up until nine months of age.  Multifocal jerks observed both before and during sleep.  Jerks could not be there when you wake up, or they might vanish.  The EEG showed no electrical seizure activity.

Etiology Of Neonatal Seizure  

1. Hypoxic ischemic encephalopathy (HIE)
   • The most prevalent cause of newborn seizures, perinatal hypoxia, is the source of HIE. Fifty to sixty percent of HIE seizures happen within the first twelve hours of life, with the remaining forty-eight hours thereafter.
   • Recurrence of these seizures decreases after the third day of life.
   • Seizures may occasionally be triggered during the rewarming stage. • Subtle seizures are more common in HIE-associated newborn seizures than focal clonic seizures or myoclonic seizures.
2. Metabolic causes
   • The second most typical reason for a group in an Indian context.  Hypoglycemia: low body weight, premature delivery, hyperinsulinemia in the child of a diabetic mother.  Hypocalcemia:  Low body weight  Preterm  Early onset (less than 72 hours) .  Late-onset - Term; particularly when given a diet consisting primarily of milk; unfavorable Ca:P ratio .  Glycine encephalopathy, Inborn errors of metabolism ,Hipomagnesemia, GLUT-1 deficiencies.  More people have pyridoxine reliance than pyridoxine deficiency.
3. Vascular causes
   • It comprises perinatal ischemic stroke and cerebral bleeding, accounting for 10–20% of all cases.  In the West, neonatal ischemic stroke ranks as the second most frequent cause.  Typically central Convulsions . A dismal prognosis.  The majority of cerebral hemorrhages happen within the first two and seventh days of life. 
   • In premature newborns, intraventricular bleeding occurs.  IP and subdural hemorrhage (SDH) The prognosis for bleeding is in between; most cases occur in term babies.  Subarachnoid hemorrhage (SAH) - Mostly in healthy-appearing term infants between days two and three of life.  The long-term prognosis is favorable.
4. Infections - 5-10%
   • Congenital - TORCH
   • Neonatal meningitis is more common than encephalitis.
5. Developmental defects of the brain - 5-10%. Defects in neural migration are among them.  Cardiac arrest.  It affects women more frequently.  They'll have gaps in their retinas.  The corpus callosum is absent.  They'll experience seizures. 
6. Neonatal seizure syndrome
   • a) Ohtahara syndrome; b) Coppola syndrome; c) Benign familial convulsions in neonates; d) Benign idiopathic convulsions in neonates . Fifth-day fits that are not familial ii. Multiple focal seizures linked to lowered CSF zinc levels. 
7. Miscellaneous causes
   • Neonatal polycythemia; inadvertent LA injection on the scalp; seizures shortly after birth; fixed dilation of the pupils; absence of the doll's eye reflex.  Withdrawal from drugs by the mother: This usually happens in the first two to three days.  Doxapram and theophylline both cause drug toxicity.  Phacomatosis: incontinentia pigmenti, tuberous sclerosis; other risk factors include CHD surgery and ECMO.

Also Read: Non-Immune Hydrops-Etiology, Investigations And Treatment

Clinical Evaluation Of Neonatal Seizures

History

• Attempt to clarify whether or not this is a seizure.
• A thorough explanation of the morphology and duration provided by the parents or other attendees.
• The newborn's state of consciousness at the moment of the seizure.
• Any variation in the color of the skin, heart rate, or blood pressure.
• Any phenomenon that triggers it.
• Any phenomenon that recurs.
• The time of day the seizure occurred.
• Seizures occurring within a span of 0 to 3 days are indicative of either HIE, IC hemorrhage, or metabolic issues.
• Sepsis, metabolic, and development-related reasons are indicated if the seizure occurred within 4–7 days of the first episode. 

Alternate history

It is appropriate to inquire about maternal infection, diabetes, and drug addiction.  A history of abrupt, sporadic increases in the movements of the fetus.

Perinatal history

 It is important to inquire about any prior instances of fetal distress, fetal harm, or instrumentation injury.

Feeding history

You should enquire about the kind and timing of feeding.  Since cow milk feeding might induce hypocalcemic seizures to start later in life, information on it should also be requested.

Family history

 It is important to inquire about any familial continuity, low IQ, or seizures during the neonatal stage (benign familial neonatal convulsions).  It is advisable to enquire about any newborn or fetal fatalities in the family.

Examination

Vitals and anthropometry should be taken into consideration. The skin should be examined for neurocutaneous indicators and dysmorphism.
Checking the fontanelle status is also necessary. Increased intracranial pressure associated with meningitis or cerebral bleeding can result from bulging anterior fontanelle. 

Pay attention to the child's tone and sensorium.  If a newborn or deep tendon reflex is present, keep an eye out for it.  Perform a fundus examination and look for any chorioretinitis symptoms.  Be alert for anomalous urine odor and hepatosplenomegaly.

Diagnostic Workup

1st line investigations

Vitals and anthropometry should be taken into consideration. The skin should be examined for neurocutaneous indicators and dysmorphism.
Checking the fontanelle status is also necessary. Increased intracranial pressure associated with meningitis or cerebral bleeding can result from bulging anterior fontanelle. 

Pay attention to the child's tone and sensorium.  If a newborn or deep tendon reflex is present, keep an eye out for it.  Perform a fundus examination and look for any chorioretinitis symptoms.  Be alert for anomalous urine odor and hepatosplenomegaly.

EEG

Routine EEG: An EEG is considered routine if it lasts for an hour.
Continuous EEG: An EEG is considered continuous if it lasts longer than three hours.  In cases of newborn seizures, continuous electroencephalography (EEG) is regarded as the gold standard of investigation. EEG with integrated amplitude. It is an alteration to a standard EEG. Its predictive value is good, and its interpretation is simpler.

Conventional EEG (Routine, Continuous)

If a traditional EEG is performed during the ictal period, or while the seizure is occurring, it can provide information regarding the kind and length of the seizure. If aberrant electrical activity is seen during the interictal phase. An illustration of a burst suppression pattern (risk of a negative neurological consequence)

Amplitude integrated EEG: recordings from a small number of electrodes (1-2 channels, 2-4 electrodes) are made with this method. Readings are obtained from these electrodes, compressed, filtered, and then projected onto a semi-logarithmic scale.

Limitations of amplitude EEG

 May cause artifacts, so it must be connected with raw EEG video. • May miss some focal seizures.  Is predictive in certain cases, such as burst suppression.

Key Point: Bloody CSF Obtained

Centrifugation should be done as soon as bloody CSF is recovered. If a clear supernatant is obtained, there is no need for concern as the tap was traumatic. Xanthochromia may indicate subarachnoid hemorrhage or intraventricular hemorrhage.

Additional investigations (2nd line investigations)

•Serum bilirubin total; hemocrit.
• Serum magnesium in hypocalcemic individuals.
• Anion gap and ABG: These are used when seizures are accompanied by vomiting, reduced eating, and sensorium alterations.
• Prepare yourself for IEM by checking your serum ammonia, ketones, etc. - It is carried out when vomiting, decreased eating, and altered sensorium are linked to seizures.
• Additional neuroimaging; • TORCH screen.
• CT: for IU infections and probable SAH/SDH infections (monitoring for cerebral calcifications).
• MRI: neural structural deficits in HIE.

Management Of Neonatal Seizures

Initial management 

Recognize a seizure and check the temperature, respiration, circulation, and airway.  If necessary, start the O2.  Obtain an IV access and request first-line hematological testing.  Hypoglycemic: f/b infusion at 6–8 mg/kg/min, with 2 ml/kg of 10% dextrose IV boluses.  Give 2 ml/kg of 10% calcium gluconate intravenously over a 10-minute period while being closely observed if blood sugar is normal.

If the seizure persists

Drug of choice - Phenobarbitone

If seizures are controlled

The first maintenance dose of phenobarbitone is administered 12 hours following the loading dose, with a daily dose maintenance of 5 mg/kg.

If seizures persist

 Phenytoin is an alternate first-line AED.  IV loading dosage: 20 mg/kg during a 20-minute period.  If seizures continue, repeat 10 mg/kg.
After seizure control is achieved, begin daily maintenance phenytoin dosage of 5 mg/kg.

If after doing all these seizures persist then 

Think about benzodiazepines.  Midazolam can also be administered at 0.15 mg/kg IV bolus, followed by IV infusion at 0.1 mg/kg/hour. Lorazepam is the recommended benzodiazepine; dosage: 0.05 mg/kg IV bolus over 2–5 min.  Midazolam is relatively faster and produces less respiratory compression than lorazepam.

If seizures are controlled now 

Wean AEDs slowly and continue phenobarbitone maintenance doses.

If seizures persist

Midazolam rate should be hiked, and if it is tolerated, then infused after every 5-10 min, maximum upto 2 mg/kg/hour.

Response Rates of Neonatal Seizures

The response rate is 40–45% if phenobarbitone (20 mg/kg) is the initial AED.  The response rate is 70% if phenobarbitone is administered at a maximum dose of 40 mg/kg.  After receiving a loading dosage of phenytoin, up to 85% of patients respond.  A lorazepam bolus can result in a response rate of up to 95–100%. 

Levetiracetam: this medication also has a favourable safety profile; loading dose: 40–50 mg/kg.  Lidocaine: An IV infusion at a rate of 2 mg/kg/hr after an initial bolus of 4 mg/kg.  Cardiac side effects: phenytoin should never be used with it

Alternative 3rd line drugs

Topiramate: 5–10 mg/kg/day; helpful for refractory seizures and infantile spasms. 

Other agents

Paraldehyde: This medication is administered intramuscularly or orally.
It has less traction. Valproate: Due to the possibility of hepatotoxicity, it is no longer used. When taking benzodiazepines, Lorazepam carries a higher risk of respiratory depression compared to Midazolam. Thus, the need for monitoring and intubation equipment arises. 

Fosphenytoin: Phenytoin's prodrug.  Fewer adverse cardiac consequences  Less harmful to delicate tissues and suitable for intramuscular administration.  1.5 mg/kg of fosphenytoin equals 1 mg/kg of phenytoin.

Additional therapy - Used in selective scenarios 

• Pyridoxine: 100 mg IV or IM in refractory seizures.
• Hypotension and apnea need to be closely monitored.
• Exchange transfusion: in drug transfers from mothers, biliary encephalopathy, LA injections, and IEMs.
• Chlorpropamide is one example.
• Phenobarbitone treatment may cause electroclinical dissociation in certain people.
• Phenobarbitone and phenytoin free drug levels need to be monitored in patients with acidosis or changed blood protein levels.
• The use of bumetanide has been discontinued because of hearing loss.
• There is a 10–30% chance of subsequent epileptic newborn episodes.

Weaning Of Aeds

• Pyridoxine: 100 mg IV or IM in refractory seizures.  Hypotension and apnea need to be closely monitored.  Exchange transfusion: in drug transfers from mothers, biliary encephalopathy, LA injections, and IEMs.
• Chlorpropamide is one example.
• Phenobarbitone treatment may cause electroclinical dissociation in certain people. Phenobarbitone and phenytoin free drug levels need to be monitored in patients with acidosis or changed blood protein levels.
• The use of bumetanide has been discontinued because of hearing loss.  There is a 10–30% chance of subsequent epileptic newborn episodes.

Prognosis In Neonatal Seizures

The primary determinant of outcome is the cause of the seizure.
Benign idiopathic newborn seizures, late-onset hypocalcemic seizures, and seizures resulting from primary SAH have excellent to good prognoses.  Poor prognosis: brain malformation-related seizures (HIE); gestational age also influences prognosis. 

Compared to myoclonic seizures and spasms, multifocal clonic seizures typically result in better outcomes. Neonatal seizures-like movements; benign nocturnal myoclonus; jitteriness; non-convulsive apnea; normal movements. 

Opisthotonus

Hyperekplexia: Hyperekplexia is defined as an exaggerated startle reaction to a tactile or aural stimulation.  Linked to hypertonia and recurrent falls.  Seizures may affect 7–12% of people.  Developmental issues and apnea frequently coexist.  Deviations in the metabolism of glycine. The recommended medication for hyperekplexia is clonazepam.

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