Introduction 

Epilepsy is one of the most prevalent neurological diseases, characterised by recurrent, unprovoked seizures. Although it is a treatable condition, it still makes up a meaningful fraction of the worldwide disease burden.¹ Furthermore, childhood epilepsy is linked to various comorbidities, some of which include cognitive and language impairment, which can be indicative of developmental delay. This article further explores the two conditions in more detail and outlines how they are interlinked.

Understanding epilepsy and developmental delays 

Epilepsy 

Definition

Epilepsy is a chronic neurological brain disease, characterised by recurring, unprovoked seizures (occurring without precipitating factors). Seizures involve involuntary skeletal muscle activity, arising from an abnormal, excessive and synchronous brain activity.² While all people with epilepsy suffer from seizures, not everyone exhibiting seizures is diagnosed with epilepsy.¹ Epilepsy has been defined by either of the below conditions by the International League Against Epilepsy Task Force: 

• Two or more unprovoked seizures occurring over 24 hours apart
• One unprovoked seizure and a probability (at least 60%) of further similar seizures after two unprovoked seizures, occurring over the next 10 years³

Types of epilepsy

The diagnosis of epilepsy has three levels of classification – the type of seizure, followed by epilepsy type and can then also be diagnosed as an epilepsy syndrome.⁴ Broadly, the key types of epilepsy include the following:

• Focal – seizures arise from one area of the brain (previously known as partial seizures) 
• Generalised – seizures affect both cerebral hemispheres from seizure onset
• Generalised and focal combined – patients exhibit both focal and generalised seizures 
• Unknown – epilepsy is diagnosed, however, a clinician cannot determine its type due to insufficient data⁵  

Febrile seizures are the most common type of childhood epileptic seizures and are typically induced by increased body temperature. However, they do not indicate epilepsy, even in recurring cases.⁶ 

The most common types of epilepsy in children include:

• Absence epilepsy – brief spells (seconds) of lost awareness, paleness, potential twitching of the eyelids, eye/head roll back, staring into the space and lack of response when addressed
• Juvenile myoclonic epilepsy – arises in puberty, muscle twitches and arm/shoulder jerking movements
• Infantile spasms (West syndrome) – typically starts in babies, bending/stretching of the body, jerking/twitching of the neck/torso
• Rolandic epilepsy – twitching of one side of the face and sometimes one arm/leg, potential numbness, tingling, issues with speech/swallowing, drooling⁷

Epilepsy causes and risk factors in children

During the neonatal period (the first 28 days after birth), some of the causes of symptomatic epilepsy may include: 

• Cortical (brain) abnormalities (e.g. infarct, haemorrhages)
• Prenatal or neonatal infection
• Acute metabolic disturbances
• Hypoxic-ischemic encephalopathy (lack of oxygen before/during birth)⁶ 

Furthermore, risk factors, such as a history of atypical febrile seizures, severe/moderate head injuries, neurological impairment, family history of epilepsy and low apgar scores at birth have also been associated with childhood epilepsy.⁸

Research suggests that around 40% of epilepsy is due to genetic factors. Many epilepsy phenotypes can be linked to specific mutations of various genes (e.g. transcription factors or ion channels) as well as specific chromosomal imbalances. However, environmental factors such as fatigue and stress should not be dismissed, given that they can influence a genetic defect.⁹

Developmental delays

Definition 

A developmental delay occurs when a child does not achieve certain developmental milestones when compared to other children of the same age.¹⁰ The delay can be considered isolated (affecting a single developmental domain), multiple (affecting >2 domains), or global (significant delay affecting the majority of developmental areas). Some of these domains with a seen impairment include speech and language, psychological, gross and fine motor, and social.¹¹

It is important to note that not all children exhibiting a developmental delay will necessarily develop a developmental disability, which is a lifelong and severe impairment affecting adaptive skills, self-sufficiency and learning.¹⁰

Developmental milestones

The five key domains of developmental milestones that children are expected to achieve as they mature are:

• Cognitive 
• Language
• Fine motor 
• Gross motor 
• Social-emotional and behavioural¹²

A good understanding of these milestones can help recognise the signs of delayed development, this way leading to earlier interventions and subsequent improved outcomes.

Causes and risk factors for developmental delays

The most common causes for developmental delays can be divided into four categories – prenatal, perinatal, postnatal and other. Numerous illnesses and causes can be linked to developmental delays, such as:

Prenatal

• Genetic disorders (e.g. fragile X syndrome, Down’s syndrome)
• Vascular causes such as haemorrhages (loss of blood from a damaged blood vessel) or occlusions (blockage of a blood vessel)
• Maternal infections
• Certain drugs e.g. anti-epileptic drugs, cytotoxic substances and toxins ie smoking
• Cerebral dysgenesis (non-formation of a cerebral hemisphere)

Perinatal 

• Prematurity (born before 37 weeks)
• Intrauterine growth restriction (impaired growth in the womb)
• Metabolic causes (e.g. bilirubin-induced neurological dysfunction or hypoglycaemia)

Postnatal 

• Trauma e.g. head injury 
• Stroke (interrupted blood supply to the brain)
• Anoxia (oxygen depletion) ie due to drowning or suffocation
• Metabolic issues such as dehydration, hypoglycaemia, low or high sodium levels
• Infections (e.g. encephalitis, meningitis) 

Other

• Malnutrition leading to vitamin deficiencies 
• Maltreatment including under stimulation 
• Maternal mental health conditions¹⁰

Developmental delays in children with epilepsy

Comorbidity 

Childhood epilepsy is often linked to cognitive and behavioural comorbidities as well as language impairment.^{13, 14} Various factors contribute to this, some of which include seizure medications and the negative effects of chronic seizures on the development of the brain.¹³  

Below are some of the relevant research findings:

• When compared to sibling controls, children exhibiting idiopathic (unknown cause) epilepsy have high-grade retention rates as well as rates of placement in special education¹⁵
• Children with recent-onset idiopathic epilepsy have been reported to show cognitive dysfunction and exhibit academic underachievement at disorder onset¹⁶
• Children with epilepsy can show impaired working memory and processing speed¹⁴
• Children with childhood absence epilepsy (CAE) have been reported to have significantly lower mean IQ and SLQ (spoken language quotient) scores, compared to the control group. Furthermore, significantly more CAE patients had a psychiatric diagnosis, with attention deficit hyperactivity disorder (ADHD) and affective/anxiety disorders being the most common¹⁷
• The severity of linguistic, psychiatric and cognitive comorbidities were linked to the seizure frequency, illness duration and anti-epileptic drug treatment¹⁷
• There is increasing evidence that certain genetic traits are common to both neurodevelopmental disorders and epilepsy¹⁸  

The effect of seizures on children's development

While it is possible that the two diseases are comorbid due to several shared genetic traits (discussed in more detail in the later section), certain epilepsy-associated factors, such as seizure frequency and the use of anti-epileptic drugs have also been linked to neurodevelopmental comorbidities while the presence of chronic seizures has been suggested to affect brain development.^{13, 17, 18}

Anti-seizure medications (ASM’s)

Certain ASM treatments have been reported to be independently linked to cognitive effects. Phenobarbital and topiramate have both been associated with cognitive issues, while topiramate is also linked to memory impairment.¹³ Furthermore, there have been reports of sodium valproate and phenytoin involvement in impaired coordination or delayed motor milestones.¹⁹ On the other hand, lamotrigine, levetiracetam and oxcarbazepine have no negative effects on cognitive development. It is therefore essential to carefully select the correct AED therapy in order to reduce the cognitive adverse effects in children suffering from epilepsy.¹³ 

Prenatal exposure to AEDs should also be considered. For instance, prenatal exposure to valproate has been linked to neurodevelopmental deficits.^{20 14} Prenatal dual or polytherapy, including carbamazepine with levetiracetam as well as topiramate with lamotrigine, was also associated with children's neurodevelopmental disorders.²¹ Lamotrigine and levetiracetam are recommended for people assigned female at birth of childbearing age, as they are safest during pregnancy. 

Seizure frequency 

Higher seizure frequency can also correlate with developmental impairment. A study reported that higher seizure frequency in 0-36 months old patients, was associated with poorer developmental testing outcomes at all time points (6, 12, 18 and 24 months of age), particularly at 12+ months.²²

Shared genetic background

As previously mentioned, certain genetic traits have been identified to be potentially involved in causing both epilepsy and neurodevelopmental disorders. The key shared genetic disorders include single-gene diseases, copy number variations and chromosomal abnormalities. The below list provides a few examples:

Single gene diseases:

• Tuberous sclerosis 
• Fragile X syndrome 
• Myocyte enhancer factor 2-related disorders
• Methyl-CpG binding protein 2-related disorders ie Rett syndrome 

Chromosomal abnormalities and copy number variations:

• Down syndrome (Trisomy 21)
• DiGeorge syndrome (22q11.2 deletion)
• Chromosome 15q11-q13 duplication syndrome¹⁸

Disease management 

The ideal treatment for children with epilepsy exhibiting developmental delays consists of maximal seizure control, whilst also trying to avoid the negative effects of ASMs. Given the potential adverse cognitive and behavioural effects, choosing the correct ASM therapy is essential.²³

There appears to be no singular best drug option that should be used for all children with epilepsy and this is determined on a case-by-case basis. The type of seizure, epilepsy syndrome as well as the drug’s efficacy and associated adverse effects will likely be the key deciding factors.²⁴ Epilepsy medication is usually prescribed and managed by a specialist neurologist or epilepsy nurse. 

Summary

Epilepsy is a chronic neurological brain disease, mainly characterised by persisting unprovoked seizures. The types of epilepsy are focal, generalised, generalised and focal combined and unknown. Developmental delay refers to when a child is not able to achieve certain developmental milestones in comparison with other children of the same age. The key domains of developmental milestones include the following: cognitive, language, fine motor, gross motor social-emotional and behavioural. Developmental delay is comorbid with childhood epilepsy and is associated with cognitive, behavioural and language impairment. The key factors potentially underlying this comorbidity are genetic traits, ASM effects, and seizures affecting the development of the brain, with higher seizure frequency linked with worse developmental testing outcomes. It is therefore essential to carefully select the correct medication, aiming to reduce the cognitive ASM adverse effects in children with epilepsy.