Encephalocele is a rare abnormality which is present at birth, characterised by the formation of a sac-like protrusion containing brain tissue and fluid from an opening in the skull. The classification of encephalocele depends on the location of the skull opening: occipital, frontal, nasal, and parietal encephalocele. The birth defect can be life-threatening; however, treatments such as surgery improve health outcomes. 

Clinical significance 

The importance of early diagnosis of encephalocele 

Encephalocele can be detected from an ultrasound as early as 13 weeks, which helps the doctors to see what area of the skull is affected, and whether the sac contains meninges (layers of membrane that cover and protect the brain), brain tissue, or both.¹ If the condition is not detected from a prenatal ultrasound, then it will be detected at birth from visible deformity of the skull and/or face. 

Early diagnosis of encephalocele is beneficial to allow time for a thorough clinical assessment of the encephalocele's location, size and sac contents. This also facilitates prompt counselling for parents, to ensure they have a deep understanding of the condition, the potential health outcomes, possible treatment options, and, in some severe cases of pregnancy termination.^{1, 2} Early detection also allows for the planning of a caesarean section in cases where the baby's head may be too big to pass through the birth canal. Furthermore, timely diagnosis enables the formation of a competent, knowledgeable multidisciplinary team to provide the best postnatal health outcome for the baby. 

Potential complications 

Although not all cases of encephalocele lead to complications, potential long-term complications from brain damage include: ¹

• Seizures 
• Developmental delays
• Vision impairment 
• Motor deficits
• Increased risk of infection, such as meningitis and encephalitis 
• Intellectual disability 
• Small head size 

Embryological development of the central nervous system (CNS) 

Neurulation - the formation of the neural tube

The central nervous system (CNS) begins to form during the third week of embryonic development and is the central processing centre for information in the human body, comprising the brain and spinal cord.³ This point of embryonic development is the neurulation stage, and is where the neural tube is formed following the presence of the notochord in the mesoderm, which enables the release of growth factors and therefore forms a thick structure called the neural plate. The edges of the neural plate elevate, creating neural folds. These folds then migrate and join at the centre, forming the neural tube as illustrated in Figure 1. 

Once the neural plate is fused and the neural tube is formed, during the third and fourth weeks of gestation, the upper part (cranial) of the tube is responsible for forming the baby’s skull and brain, and the lower part (caudal) of the tube is the spinal cord. 

When problems occur during the neurulation stage of embryological development, causing the incomplete closure of the neural tube, this gives rise to the birth defects known as neural tube defects (NTDs). 

Neural tube defects (NTDs) and encephalocele 

Neural tube defects occur during the first month of embryological development; the most common types of NTDs are spina bifida, anencephaly and encephalocele. Encephalocele is one of the rarer types of NTD, affecting around 350 babies born per year, and is a direct result of the incomplete closure of the top part of the neural tube.⁴ Consequently, the formation of the skull is also incomplete, allowing the baby’s brain tissue and membranes to protrude through the gap, presenting as a sac-like structure on the baby’s head. 

Pathogenesis of encephalocele 

Closure of the neural tube 

Following the process of the folding and fusing of the neural folds, the neural tube is normally formed by day 28 of embryological development. The upper part of the neural tube, referred to as the cranial region or anterior neuropore, is usually closed/formed by day 24 of embryological development, and the lower region of the tube, referred to as the caudal region or posterior neuropore, is typically completed by day 28. The closure of the neural tube is significant to ensure the baby's skull and brain are able to develop properly and to avoid NTDs. This closure ends the primary stage of neurulation. 

Secondary neurulation takes place between weeks five and six of embryological development and is the stage where the caudal region of the neural tube forms the spinal cord via the process of a cluster of cells condensing and hollowing out (cavitates).⁵ However, encephalocele is a defect caused only by the incomplete closure of the cranial region of the neural tube in the primary stage of neurulation. 

Genetic factors 

Although the exact cause of encephalocele is unknown, there are links made between genetic and environmental factors contributing to the development of the condition. Encephalocele is more prevalent in individuals who have a family history of neural tube defects, indicating inherited predispositions have a role in the development of the condition. Additionally, studies have also proven that environmental factors such as exposure to TORCH infections (toxoplasma, rubella, cytomegalovirus, herpes simplex virus) have directly contributed to multiple cases of encephalocele.⁶

Scientists have proposed that environmental exposures combined with inherited susceptibility genes increase the risk of babies developing encephalocele. In addition to maternal infections, environmental factors also include low folate levels, some medications, high body temperature/fever and poor maternal health conditions such as diabetes. 

Environmental factors 

Nutritional deficiencies have been associated with the development of encephalocele; these deficiencies include folic acid and B12. 

Studies have previously established a connection between the risk of NTDs and low folate levels in mothers.⁷ Folic acid plays a major role in the production of nucleotides, so when pregnant individuals have folic acid deficiencies, this consequently impairs the role of the nucleotides in regulating and repairing DNA and RNA expression, which enables damaged DNA to mutate and potentially impair the process of neurulation.

Maternal conditions such as diabetes, drug exposure, and radiation are also associated with environmental factors with NTDs. Poorly controlled diabetes may result in an increase in oxidative stress, which causes the dysregulation of developmental genes that are essential for processes like neural tube closure, therefore resulting in an increased risk of encephalocele.⁸ 

Types and locations of encephalocele 

There are several types of encephalocele categorised by the location of the protrusion, including occipital, frontal, nasal, parietal, and sphenoidal, which are areas in the brain. 

Occipital encephalocele 

The most common form of encephalocele is occipital, presenting as a protrusion of various sizes over the occipital bone, situated at the back, lower region of the skull. Occipital encephalocele accounts for around 75% of encephalocele cases.⁹ This type of encephalocele can also cause concurrent hydrocephalus – build-up of fluid, putting pressure on the brain, which is prevalent in 40%-60% of cases – as well as causing seizures and neurological and motor development delays.

Frontal encephalocele 

Frontal encephalocele (also referred to as Frontoethmoidal) is less common in comparison to occipital, with a prevalence of around 20% of cases.¹⁰ This primarily affects the region of the skull between the nose and forehead and may cause neurological issues due to the proximity of the protrusion to important brain regions. Babies born with this type of encephalocele have increased life expectancy and better function, as they have less severe clinical implications than protrusions at the back of the head. 

Diagnosis 

Encephaloceles are diagnosed prenatally via an ultrasound if they are large enough, or in most cases, where the encephalocele is smaller, diagnosis will be made at birth when it is more visible. If the diagnosis is made prenatally, an MRI or CT scan will usually confirm the condition and its severity, depending on the location and contents of the sac-like protrusion. Postnatal diagnosis involves a physical exam, and in some cases, genetic testing may be performed to identify if the encephalocele is sporadic (most commonly) or part of a genetic predisposition. 

Treatment and management

The most common form of treatment for encephalocele is surgery, performed under general anaesthesia to repair the skull defect and reposition any displaced brain tissue within the skull. The timing of the surgery is dependent on the thickness of the membrane covering the sac; a thin membrane suggests the necessity to postpone the surgery from taking place soon after birth to prevent infection and damage to the affected area. A thicker layer of skin follows the recommendation of delaying the surgery for one to two months to enable the growth and development of the baby.

The prognosis is variable depending on the location and amount of brain tissue protruding through the skull. Additionally, the outcome is also subject to other medical issues that may be present. The post-surgery outlook is most commonly positive, enabling most children to lead a normal life, and a few present long-term effects such as vision, hearing and breathing impairments. Therefore, it emphasises the benefit of early diagnosis and surgery. 

Furthermore, long-term treatment of the defect addresses the management of neurological issues and facial deformities, which may also entail surgery. 

Summary

Encephalocele is a rare congenital condition caused by a defect in the neural tube during the early stages of embryonic development as a consequence of incomplete closure of the neural tube during neurulation. The defect is characterised by a protrusion of brain tissue through the opening in the skull, classified by the location of the protrusion. The development of encephalocele is linked to the incomplete closure of the neurulation tube during the third and fourth weeks of pregnancy, emphasising the importance of both genetic and environmental factors, including folate deficiency, TORCH infection exposure, maternal diabetes and drug exposure on neural tube closure. 

Early diagnosis through ultrasound and confirmatory imaging allows for timely medical decision-making, consisting of parental understanding and counselling and multidisciplinary care planning to ensure the baby has the best treatment and management plan. Early surgical intervention promotes favourable outcomes, although the general prognosis for encephalocele is variable, and often long-term management entails support for neurological and developmental issues. 

Ultimately, a thorough understanding of the embryological development and pathogenesis of encephalocele is essential for improving prevention, early diagnosis, treatment and management of the condition. An insight into the development and pathogenesis of encephalocele permits medical teams to enhance prognosis through prompt action and complete, coordinated treatment plans.