Pediatric Epilepsy Syndromes with Favourable and Unfavourable Outcome : Explained

Pediatric Epilepsy Syndrome, which have a good outcome, are further grouped into groups as follows:

• Neonatal onset 
  • Benign Neonatal Convulsions or Benign Idiopathic Neonatal Convulsions 
  • Benign Familial neonatal conventions
• Later age onset (childhood-onset or a post infancy onset)
  • Rolandic epilepsy 
  • Benign childhood epilepsies or benign epilepsies with occipital spikes
  • Childhood Absence seizures
• Adolescent onset:  Juvenile absence seizure/ Juvenile myoclonic epilepsy.

Let us read about all the above-mentioned Syndromes in detail. The EEGs related to these seizures can be read and understood by signing up for the PrepLadder app.

Benign Neonatal Convulsions

Benign Neonatal Convulsions are also known as Benign Idiopathic Neonatal seizures. They usually start on the fifth day of life and are called fifth-day fits. They are self-limited, Non-familial seizures. The onset of this condition is in neonates and usually happens around day five of life. 

The morphology is in the form of apneic seizures. Hence, there are only episodes of apnoea associated with tachycardia in these patients, and sometimes they may have focal motor seizures.

EEG abnormalities in Benign Neonatal Convulsions

Benign Neonatal Convulsions EEG has abnormalities not only during the seizure but also has a characteristic pattern. The inter-ictal EEG in between the seizure is called Theta point alternant. Sharp waves with a 4-7 Hertz frequency will be intermixed with Sharp spikes and non-reactive to stimuli. It will occur in the sleep state as well as in the awake state. It can persist for as long as Twelve Days, even after the seizures have stopped. Ictal EEG shows multifocal seizure activity in these patients. 

The cause of Benign Neonatal Convulsions is unknown. However, many patients are found to have low CSF zinc levels. 

Treatment of Benign Neonatal Convulsions

Most patients do not require therapy and stop spontaneously in a few weeks. If there is a prolonged seizure episode, responds well to IV benzodiazepines or IV Phenobarbitone. There is no long-term adverse neurological outcome. 

Benign Familial Neonatal Convulsions

Benign Familial Neonatal Convulsions is a neonatal familial seizure disorder; the inheritance is Autosomal Dominant. The genes involved are:

• KCNQ2 gene on 20q occurring in 50% of cases, most common and codes for voltage-gated potassium Channels
• KCNQ3 gene on 8q and codes for voltage-gated potassium Channels
• SCN2A gene on 2q codes for sodium Channels.

The Age of onset of Benign Familial Neonatal Convulsions is 2-4 days of life; remit by 2-15 weeks of age. Morphological changes seen here are Ocular deviation, Tonic, Multifocal Clonic, and Motor Automatisms.

EEG changes in Benign Familial Neonatal Convulsions

Interictal EEG appears Normal. 

Ictal EEG shows Multifocal epileptiform discharges.

Management of Benign Familial Neonatal Convulsions

In most cases, no specific therapy is needed. For others, Oxcarbazepine can be given.

There is no role for Levetiracetam.

The Long-Term Outcome appears good, with no long-term cognitive or neurological abnormalities. Fenichel says about one-third of these patients may develop febrile seizures, and another one-third may develop future epilepsy. Nelson says about 16% of patients may develop future epilepsy.

Rolandic Epilepsy

The current name is Benign Childhood Epilepsy with Centrotemporal spikes, also called rolandic spikes. The cause is unknown, but it is Autosomal Dominant in many cases. The age of onset is 3-10 years, peaks at 7-8 years, and outgrows by 13-15 years.

Morphology: it is a nocturnal seizure, and the child typically wakes up at night with focal seizures and preserved consciousness and comprehension. It mostly involves the face. Drooling of saliva from one side & may face an inability to speak. Paresthesias: Most buccal and throat tingling is present. Tonic-clonic contractions on one side of the face, drooling, and inability to speak may be seen. Sudden night twisting of the face on one side, along with speech problems. It may last for 1-2 min.

Rarely do patients have some impairment of consciousness. Some may progress to secondary generalization, especially if nocturnal seizures occur at <5 years of age.

EEG of Rolandic Epilepsy

• Centrotemporal spikes, wide-based, more in drowsiness & sleep 
• Fenichel says the spike discharge frequency does not correlate with the subsequent course.

Management of Rolandic epilepsy

• DOC: Oxcarbazepine / Carbamazepine 
• Levetiracetam 2nd line.
• Good Outcome: Many outgrow even without therapy. 

Panayiotopoulos Syndrome

Panayiotopoulos Syndrome is a Benign form of Epilepsy With Occipital Spikes. The age of onset is 3-6 years, with some presenting as late as 14 years. Focal Seizures are more common in sleep and are often associated with ictal vomiting. There is a Loss of awareness. Autonomic features like pallor, sweating, etc., can occur. Irritability, behavioral issues, and tonic eye deviation are also seen. 

EEG changes in Panayiotopoulos Syndrome:

Ictal EEG shows Posterior slowing and interictal EEG shows high-amplitude 2-3 Hz sharp and slow wave complexes from the posterior quadrants.

Treatment of Panayiotopoulos Syndrome

Respond well to usual AEDs. In most cases, remission is seen 1-2 years after onset.

Absence Seizures

Absence Seizures are also called Petit Mal Seizures. According to Fenichel, Absence Seizures can occur in 4 clinical entities: Childhood Absence Epilepsy (the most common association), Juvenile Absence Epilepsy,  Juvenile Myoclonic Epilepsy, and Epilepsy with grand mal on awakening.

Childhood Absence Epilepsy

The age of onset is 5 to 8 years in most cases. Overall, females are slightly more commonly affected than males. Many cases show Autosomal Dominant inheritance. Most patients are developmentally normal with normal cognition. Multifactorial pathogenesis is implicated. Genetic locus: GABRG2( Gamma-aminobutyric acid receptor ) on 5q34. Early-onset cases may show mutations in the SLC2A1 gene➡ CSF Glucose Transporter or GATM gene. Nelson Says: If early age of onset <4 yr, suspect Glucose Transporter Defects. These patients will show resistance to therapy.

Morphology of the Seizure

The seizure is often precipitated by hyperventilation for about  3 to 5 minutes. Multiple episodes( upto 100 each day) of each approximately  5-10 seconds. The patient will have a brief, Vacant, Staring Look. There is no Post-Ictal Confusion and no Aura. No Loss of tone/motor movement in limb. Some may have Fluttering of eyelids or maybe  transient ocular deviation. Rarely shows simple automatisms: lip smacking, picking at clothes.

EEG of Childhood Absence Epilepsy

Childhood Absence Epilepsy shows a 3 Hz spike and slow wave discharge. Although discharge can be seen in all electrodes, it is very prominent in the central and frontal electrodes of the EEG. 

Juvenile Myoclonic Epilepsy (JME)

Juvenile Myoclonic Epilepsy (JME) is also called Janz Syndrome. Most common generalized epilepsy in adults: Upto 5-10% of all epilepsies. Gender Preponderance is controversial: Some say F>M; others F=M. The age of onset is 12-18 years. Most cases show Autosomal Dominant inheritance. The Genes implicated are CACNB4, GABRA-1, and  EFHC-1, also called Myoclonin-1.

Morphology of Juvenile Myoclonic Epilepsy (JME)

The Hallmark of Juvenile Myoclonic Epilepsy (JME) is Myoclonic Jerks (100%). These are Brief, Bilateral, Repetitive, and Flexor Jerks in limbs. Often occurs in the morning, In an awake state- Intact Consciousness. Frequent falls or dropping of objects from hands is an early clue. Precipitated by Photic stimulation, Sleep Deprivation, and Alcohol. EEG: 4-5 Hz Polyspike and Slow Waves Discharge. 

GTCS may develop in upto 50-90% of cases later.

Juvenile Absence Seizures are Seen in upto 25-30% of cases.

Treatment Of Juvenile Myoclonic Epilepsy (JME)

Drug of Choice: Valproate which is giving life long 

Alternative therapies are Levetiracetam, Lamotrigine.

Frequently Asked Questions: 

Q: What is the drug of choice for Juvenile Myoclonic Epilepsy (JME)?

Answer: Valproate 

Q: What is the drug of choice for the Management of Rolandic epilepsy?

Answer: Oxcarbazepine / Carbamazepine

Q: What is the gene defect in Benign Familial Neonatal Convulsions?

Answer: KCNQ2 gene on 20q

Q: Which disease is known as fifth-day fits disease?

Answer: Benign Neonatal Convulsions are also known as Benign Idiopathic Neonatal seizures. They usually start on the fifth day of life and are called fifth-day fits.

Pediatric Epilepsy Syndromes with Unfavourable Outcome

Common Pediatric Epilepsy Syndromes which are severe and who have an unfavorable outcome are further grouped into:

• Onset less than one year of age/Onset in infancy: includes Otahara syndrome, Dravet Syndrome, and infantile spasms/West syndrome.
• Childhood-onset: Lennox Gastaut syndrome and Landau Kleffner syndrome. 

Let us read about some of them one by one.

Ohtahara Syndrome

Ohtahara Syndrome is also called EIEE (Early Infantile Epileptic Encephalopathy). There is no myoclonus. It is a severe, early-onset epileptic disorder, starting in 1st 2 months of life. The hallmark of Ohtahara  Tonic seizures with progressive encephalopathy are as follows. 

The Genes Associated

• Syntaxin-Binding Protein-1/STXBP1 on 9q34.1, produces EIEE Type 4
• ARX gene on Xp22.13 
• STK9/CDKL5 on Xp22

Many cases are also associated with brain malformations

Diagnosis and Therapy of Ohtahara Syndrome

• EEG - Burst  suppression pattern 
• Treatment in this patient is difficult.
• Seizures are usually refractory.
• Many respond to drug ACTH or vigabatrin or topiramate
• Most cases develop features of the west syndrome in late infancy.

Differential Diagnosis of Ohtahara Syndrome

Early Myoclonic Epileptic Encephalopathy(EMEE) has a similar age of onset of fewer than 2 months. It has Similar encephalopathy and EEG Findings to Ohtahara syndrome. EMEE shows Severe myoclonic seizures instead of tonic seizures seen in Ohtahara Syndrome. It has a poor response to therapy.

Dravet Syndrome

• It is also called Severe Myoclonic epilepsy of infancy (SME-I).
• Considered to be febrile seizure-associated epilepsy: onset in infancy.
• Mostly due to de novo mutations, sometimes AD inheritance.

Genes in Dravet Syndrome

• SCN1A implicated in 80% cases: Loss of function mutations on 2q24.
• SCN2A, SCN18, and GABRG2 genes are the other genes associated.

Clinical Spectrum of Dravet Syndrome

• Begins initially as Complex Febrile Seizures
• Often, focal unilateral clonic seizures recur in clusters every 1-2 min, precipitated by fever, and are usually more prolonged.
•  Sometimes Generalized FS or Febrile SE
•  As age increases, seizures start occurring with low-grade fevers and then afebrile seizures.
•  During the 2nd year of life, Myoclonic seizure, atypical Absence seizure, Focal seizure, and development delay become apparent.

Diagnosis of Dravet Syndrome

• Diagnosis made by Phenotype along with Genetic Testing

Treatment of Dravet Syndrome

• Effective 1st Line medications include Valproate and Clobazam
• Stiripentol is very effective and can interact with other drugs that should be monitor 
• Levetiracetam, Topiramate, Zonisamide, and Rufinamide can also be effective.
• Cannabinoids in age >=2yr is FDA Approved. Start @ 5 mg/kg/day in 2 divided doses orally and increase gradually to 10-20 mg/kg/day.
• Ketogenic Diet may be useful in refractory cases
• Avoid Na+ channel-blocking agents as well as Barbiturates 
• Genetic Counselling is recommended.

Differential Diagnosis of Dravet Syndrome

Generalized Epilepsy With Febrile Seizures Plus (GEFS+) is Due to similar gene mutations as Dravet Syndrome but milder.

Autosomal Dominant & a variable phenotype, having Positive family history. Presents as febrile seizures can progress to afebrile seizures as well. Responds to similar drugs as for Dravet Syndrome; some may show remission in later life as well.

West Syndrome

The Age of onset is 2-12 months, peak onset is between 4-7 months, and onset is always in infancy. The classic triad of  Infantile spasm, developmental regression, and on Hypsarryhthmia on EEG is seen.

Etiology and Types of West Syndrome

i. Cryptogenic: Idiopathic

ii. Symptomatic: (previously called as secondary West syndrome ): Underlying abnormality, e.g., Perinatal asphyxia, structural brain disorder and neurocutaneous  syndrome (e.g., tuberous sclerosis).

Genetic Basis of West Syndrome and Its Epidemiology

In Western countries, the cause of West syndrome is genetic > perinatal asphyxia. In India, first occurs perinatal asphyxia > genetic syndrome. A common gene mutation indicated in males with west syndrome is the ARX gene mutation. This child will also have ambiguous genitalia and cortical migration defects.

Clinical Spectrum in West Syndrome

The Hallmark finding in West Syndrome is infantile spasms, also called infantile epileptic spasms. Spasms like jerks commonly involved in limbs, trunk, head and neck. They are usually symmetrical and can also be asymmetrical. Upper limbs are more frequently involved than lower limbs. These spasms are usually precipitated by other drowsiness or awakening from sleep. These spasms tend to occur in clusters, with about 10-100 spasms per cluster in each patient. Infantile spasms frequency and control directly correlate with a decline in the developmental milestone. Flexor spasms are more common than extensor spasms.

ECG Findings in West Syndrome

The classic ECG finding in West syndrome is hypsarrhythmia, a chaotic, high-voltage, variable, high-amplitude electrical activity interspersed with occasional sharp spikes. In this, all waves merge into each other, and this is generalized wave activity.

Diagnostic Categories of West Syndrome

Interictal EEG shows hypsarrhythmia (or it is a variant) along with either electroclinical documentation (ictal EEG showing electrodecremental response) or an Infantile home video showing the cluster of spasms. In that case, it is considered as Confirmed West Syndrome. When clinical history is suggestive of spasms, but EEG shows Multifocal discharges. Still, if not hypsarrhythmia or a variant, it is said to be Probable West Syndrome which has high diagnostic certainty. When the history of spasms is doubtful, and EEG shows Multifocal discharges and not hypsarrhythmia or its variant. It is known as Possible West Syndrome, which has low diagnostic certainty.

Management of West Syndrome according to AOCN 2021 Guidelines

• The therapy of choice is Hormonal Therapy. Adrenocorticotropic hormone (ACTH) is the preferred agent. A high-dose regimen is used, in which ACTH is 150 U/m² or 6 U/kg intramuscularly once for two weeks. Clinical response develops in about seven days.
• If unavailable, a high prednisolone dose at 4 mg/kg/day is used for 2 weeks. Follow-up EEG is also required at 1,2 and 4 weeks.
• Vigabatrin = VGB is Given if ACTH or steroids fail or are contraindicated. It is preferred over ACTH in West Syndrome associated with Tuberous Sclerosis. The problem with vigabatrin is the risk of retinal toxicity in 30% of patients, especially if given for more than 6 months, and thus ophthalmological evaluation is needed in these patients.
• If both Hormonal Therapy And VGB fail, Trials of BZD, Valporate, Topiramate, or Zonisamide can be given.
• Dietary Therapy
  • If the above hormonal or VGB, along with additional AED, also fails, then it is better to start a Ketogenic Diet for 3 months as well as high fat, low carb, and restricted protein diet.
  • In resource-limited settings, a patient can consider a Modified Atkins Diet.
• Epilepsy Surgery
  • In severe West syndrome associated with surgically correctable lesions. For example, Cortical Dysplasia and Structural Anomalies in Neurocutaneous syndromes.

Lennox Gastaut Syndrome (LGS)

Lennox Gastaut Syndrome (LGS) is a severe, refractory, progressive epileptic encephalopathy. The age of onset of Lennox Gestalt syndrome is 2-10 years. Almost 60% are found to have an underlying cause, for example, TSC, Brain injuries, etc. About 20% of patients evolve from preceding West syndrome. Most children are neurologically abnormal before seizures begin. A Triad Of:

• Developmental delay
• Multiple refractive seizures:  atypical absence, Myoclonic, atonic, and tonic.
• Abnormalities typically include 1-2 hertz spike and slow waves, and polyspike bursts in sleep and a slow background in wakefulness.

Along with EEG, an MRI brain is also indicated in most patients.

Treatment of Lennox Gastaut Syndrome (LGS)

The first-line drugs are Valporate, but seizures are often refractory, requiring multiple AEDs like Topiramate, Lamotrigine, Felbamate, Clonazepam, etc. Rufinamide is also effective in many patients. Other modalities include ketogenic diets such as cannabinoids, corticosteroids and IVIG. Vagal nerve stimulation and Corpus Callosotomy for refractory drop attacks. Surgery can be a last resort.

Landau-Kleffner Syndrome (LKS)

Landau-Kleffner Syndrome (LKS) has an Autoimmune or genetic basis—GRIN2A Mutations. The Age of Onset is 3-6 years, as per Nelson's 21st Edition. Patients experience Progressive loss of language skills and verbal Auditory Agnosia—the inability to comprehend speech. At least 70% of patients develop seizures—multiple types—focal and T-C. 

EEG findings in Landau-Kleffner Syndrome (LKS) 

EEG: Bitemporal areas show high amplitude spike and wave discharges, esp during NREM sleep. Thus, a sleep EEG is indicated. EEG may become normal later. Some patients may show Electrical Status Epilepticus in Sleep (ESES)

Differential Diagnosis of Landau-Kleffner Syndrome (LKS)

A differential diagnosis of the LKS is given below:

• CSWS = Continuous Spike Waves In Slow Wave Sleep
• ESES can occur in >85% of the slow wave sleep
• Discharges are usually frontal or generalized.
• Developmental delay is global.
• Therapy is similar to that of LKS.

Treatment of Landau-Kleffner Syndrome (LKS)

For seizures, valproate and clobazam are the first-line drugs. For aphasia, nocturnal diazepam is followed by oral steroids. IVIG may be prescribed to the patients

Frequently Asked Questions:

Q: Why Do Infantile Spasms Happen?

Answer: There are three processes implicated, which can be singly or in combination.

• Increased corticotropin-releasing hormone (CRH).
• Sodium channels blockade.
• NMDA receptor stimulation.

Q: Which drug AED is used for bridge therapy?

Answer: Clonazepam.

Q: What are subtle spasms?

Answer: Subtle Spasms are episodes of activities such as a head nod, facial grimacing, eye movement, yawning, and gasping associated with hypsarrhythmia.

Q: What are Infantile spasms?

Answer: Infantile Spasms or single spasms variant (IISV) occur singly and not in clusters.

Q: What are Epileptic Spasms?

Answer: Epileptic Spasms are the clinical spasms associated with an epileptic form of EEG.

Also Read: Hearing Loss in Nicu Graduates

Hope you found this blog helpful for your NEET SS Pediatrics Neurology Preparation. For more informative and interesting posts like these, keep reading PrepLadder’s blogs.