Continuing Education Activity

Hydranencephaly is a rare congenital abnormality in which the cerebral hemispheres are absent with the basal ganglia, brainstem and meninges preserved. It is commonly caused by infarction secondary to bilateral internal carotid artery obstruction. In some cases, patients appear normal at birth. This activity reviews the treatment and management of hydranencephaly and highlights the role of the interprofessional team in improving care for patients with this condition.

Objectives:

• Identify the etiology of hydranencephaly.
• Describe the appropriate evaluation of hydranencephaly.
• Outline the management options available for hydranencephaly.
• Summarize interprofessional team strategies for improving care coordination and communication to advance the care of patients with hydranencephaly and improve outcomes.

Introduction

Hydranencephaly is a rare congenital post-neurulation disorder that occurs during the second trimester characterized by the destruction of the cerebral hemispheres, which are replaced with a membranous sac filled with cerebrospinal fluid (CSF).[1][2] The cranial cavity may have remnants of glial tissue and ependyma, especially along the falx and close to the diencephalon.[2] The cranial vault and meninges are intact. It is most commonly caused by a vascular insult involving the anterior circulation. Midbrain structures such as the basal ganglia, brainstem, and posterior fossa structures are present.[3] Patients at birth can appear normal with intact primitive reflexes. With time, they can present with macrocrania due to increased CSF pressure or less commonly with microcephaly. Diagnosis can be made in-utero with ultrasonography. Treatment is usually supportive, although in some cases with hydrocephalus, shunting of the CSF may be considered.[4][5][6]

Etiology

The etiology behind this condition is usually unknown. Different causes have been postulated.

• Ischemic stroke (infarction): Bilateral occlusion of the supraclinoid segments of the internal carotid artery (ICA) and, in some cases, the middle cerebral artery (MCA) can occur - usually between the 8th and 12th weeks of gestation. This leads to the absence of structures perfused by the ICA/MCA and preserved structures perfused by the posterior cerebral artery and the basilar artery.[2][4][5] This is the most commonly proposed mechanism.
• Infectious: An intrauterine infection may cause necrotizing vasculitis and lead to hydranencephaly. Intrauterine infections such as toxoplasmosis and viral infections (enterovirus, adenovirus, parvovirus, cytomegalovirus, herpes simplex, Epstein-Barr, and respiratory syncytial viruses) may be responsible.[3][4]
• Hypoxia: Fetal hypoxia, especially with severe maternal carbon monoxide exposure. This leads to diffuse hypoxic-ischemic brain necrosis.[4]
• Syndromic/genetic: Mutations in the COL4A1 gene, LAMB1 gene, and the PI3K-Akt3-mTOR pathway.[7][8][9]
• Leukomalacia: An extreme form of leukomalacia that develops multiple cystic cavities that end up coalesced inside the cranial cavity.[4]
• Toxic exposure: Maternal exposure to toxins, such as cocaine, smoking, estrogens, and sodium valproate, may cause hydranencephaly.[4][5]
• Twin pregnancy: The death of a co-twin in utero may lead to the development and accumulation of embolic material from the deceased twin.[4]
• Other: Rare syndromes (Fowler syndrome), deficiency of factor XIII (fibrin stabilizing factor), and intracerebral hemorrhage may be a cause.[5][10]

Epidemiology

Hydranencephaly is a rare condition and is rarely seen nowadays due to therapeutic abortions. The incidence may vary from 1 in 10,000 to 1 in 5,000 (0.01% - 0.02%) of pregnancies.[4][11][12] There is no difference between males and females.

A study performed in the United States with the population of Texas showed an incidence rate of 1.4 to 2.8 per 100,000 live births.[13] A study in a Japanese population found an incidence of 2.1 per 100,000 live births.[11] Another independent study found that 1% of patients with hydrocephalus were diagnosed with hydranencephaly.[5]

Although there is no established model of transmissions between mother and fetus, a few cases have been linked with autosomal recessive inheritance. This mode of transmission occurs in patients with the association of a rare genetic syndrome and/or conditions listed below.[2][14]

• Fowler syndrome: Also known as proliferative vasculopathy and hydranencephaly–hydrocephaly syndrome. It has an autosomal recessive inheritance, in which a mutation in the FLVCR2 gene in chromosome 14q24.3 occurs. It is a proliferative glomeruloid vasculopathy that results in the destruction of the cerebral mantle, deep gray matter, brainstem, cerebellum, and spinal cord.[10][14] 
• Trisomy 13
• Renal aplastic dysplasia
• Polyhydramnios
• Arthrogryposis
• Poly-valvular heart disease

Pathophysiology

The pathophysiology of hydranencephaly is still controversial, however, most studies suggest that the damage caused to the brain is related to bilateral internal carotid artery occlusion. As such, hydranencephaly is categorized into a group of circulatory developmental encephalopathies. Even though the most probable hypothesis behind the pathophysiology of hydranencephaly is a vascular anomaly, there have been autopsy reports where the internal carotid arteries were intact. An intact internal carotid artery does not exclude it as the key element for the development of hydranencephaly since it has been demonstrated that the internal carotid arteries could revascularize after the damage has already been done.[5] Characteristics that suggest the involvement of the internal carotid artery are:

• The anomaly presenting in hydranencephaly follows the anatomic distribution of the brain supplied by the internal carotid artery. The structures supplied by the posterior circulation (cerebellum, brain stem, thalamus, basal ganglia, and choroids plexus) are preserved.[2][3]
• Internal carotid artery anomalies demonstrated by angiographic studies and in autopsy reports.

Two different hypotheses to explain the severe brain damage that occurs in hydranencephaly are suggested.

• Encephaloclastic process (destructive theory): Hydranencephaly occurs most commonly during the 2nd trimester. At this point, the events occur after neural migration but before synaptogenesis. This means that the destruction of the brain occurs after the brain and ventricles have formed in utero due to this encephaloclastic process.[5]
• Dysontogenic process: Disruption of the organogenesis at its early stages.[5]

Although a predisposing molecular/cytogenetic anomaly has not been demonstrated to be linked to hydranencephaly, it cannot be excluded. Molecular dysfunction and cytogenetic anomalies, such as triploidy, could be involved in the development of hydranencephaly in some patients.[5]

• Mutation in COL4A1: Reported in a patient diagnosed with porencephaly that resembled hydranencephaly.
• Mutation in PI3K-AKT3-mTOR: Specifically for neurodevelopmental anomaly such as megalencephaly.
• Triploidy: Had been reported to be the cause of hydranencephaly in some patients presenting with hydrocephalus.

The most accepted pathophysiology behind the development of hydranencephaly is a bilateral vascular insult to the internal carotid arteries early during the neurogenic phase. The pathogenesis mechanism itself may start as early as the 8th to 12th weeks of gestation, and the diagnosis of hydranencephaly has been reported as early as the 12th week (1st trimester).[3] Damage to the brain usually is appreciated by diagnostic studies as early as the 13th to the 26th week of pregnancy (2nd trimester) when hemispheres and falx have been formed. Hydranencephaly is a disruption and not a malformation caused by intrauterine ischemia along the areas irrigated by the internal cerebral arteries.[2][3][5][12]

Due to the absent development of the cerebrum, the intracranial pressure decreases, which leads to a collapse and accumulation of the skull which in turn leads to microcephaly. The fetal brain disruption sequence (FBDS) is the term used to describe this progression from hydranencephaly to microcephaly.[15]

History and Physical

Most patients with hydranencephaly die before birth. During gestation, the mother feels normal fetal movements, and the abdominal growth is normal.[4][5] A child born with hydranencephaly may appear completely normal at birth. The head circumference and spontaneous reflexes, such as sucking, swallowing, crying, and moving all extremities spontaneously may be normal at birth. Some patients present with skull and upper facial features that may have a degree of deformity if the intracranial pressure inside the skull was increased. Those with more severe disease may present at birth with evident symptoms such as seizures, myoclonus, and respiratory difficulty.[4][5][12]

Patients who appeared normal after birth start developing a few weeks later, more worrisome signs such as hyperirritability, increased or decreased muscle tone (hyper/hypotonia), increase in head circumference, and wide-open anterior fontanelles. These signs become rapidly more pronounced after several more weeks. Months later, patients can develop seizures and hydrocephalus. Hearing is usually preserved, but in rare cases, sensorineural hearing impairment is noted. Visual impairment is noticeable, and most of the children have cortical visual impairment from the absence of visual cortex but with normal eyes.

Other symptoms/signs that may appear later are:[4][5]

• Lack of growth
• Spastic diplegia
• Cognitive delay
• Hypertelorism
• Bilateral optic nerve hypoplasia
• Diffuse chorioretinal atrophy
• Pigment clumping
• Dysplastic retina
• Blindness

Evaluation

The majority of patients are diagnosed during pregnancy. Several techniques can be used to make the diagnosis. A regular ultrasound can be used to make a preliminary diagnosis of hydranencephaly. To confirm the diagnosis, a level 2 or higher ultrasound needs to be used.[4][5] Another study used to diagnose hydranencephaly during pregnancy is magnetic resonance imaging (MRI), although it is rarely used in pregnant patients.[5] If the diagnosis is not made during the pregnancy, postnatal diagnosis may be delayed from weeks to months, since patients may initially appear and function normally.[4] The gold standard for diagnosis is a brain MRI since it can differentiate between other similar diagnoses, such as severe hydrocephalus and holoprosencephaly.[5]

• Ultrasound: Performed during the 21 to 23 weeks of gestation. Absence of cerebral hemispheres, replaced with homogeneous echoic material. Preservation of thalami, brainstem, and cerebellum. Although most commonly used during pregnancy, this test can be also used during the postnatal period to obtain a diagnosis.
• Brain MRI (gold standard): Absence of supratentorial brain parenchyma that is replaced with CSF. It can contain remnants of parenchyma, especially of the occipital and orbitofrontal areas. The falx, cerebellar hemispheres, and brainstem are usually present.
• Head computed tomographic scan: Very similar findings as described in MRI, although MRI is more accurate and precise.
• Transillumination: Place a flashlight at the base of the head, and if hydranencephaly is present, the light will be reflected and seen throughout all the scalp/head since it is filled with CSF. It can be used for diagnosis if no neuro-radiological imaging is available and if by physical examination, it is highly suspected.

Other ancillary tests performed:[5]

• Electroencephalogram: Shows an absence of electrical activity in all electrodes and a diffusely flattened tracing, or very low amplitude, no background, and slow-wave with poor modulation.
• Brainstem auditory evoked response test: Used to confirm the loss of cortical function but with preserved brainstem function.
• Auditory: Used to confirm the loss of cortical activity with the preservation of brainstem functions (auditory middle latency responses and cortical auditory evoked responses).
• Ocular: Used to confirm the loss of cortical activity with preserved brainstem function (strobe electroretinograms, strobe-flash visual evoked responses). In some cases, a total absence of visual evoked potential can be present.
• Digital subtraction angiography: Used in some cases to evaluate the patency of the internal carotid arteries.
• Brain magnetic resonance angiography: Used in some cases to visualize the internal carotid arteries.

Treatment / Management

Treatment consists of supportive management for the symptoms and management of associated morbidities and/or complications. The prognosis of the patients with hydranencephaly is poor. Patients affected by this condition usually die in-utero. Those that survive usually die within the first year of life. For these reasons, therapeutic abortion is an option if diagnosed during pregnancy. If the diagnosis is confirmed during pregnancy, discussion in detail with all family members is done. Given the prognosis, to prevent or reduce maternal morbidity (medical, psychological, and economical), the option of medical abortion is discussed and offered. This could be done as late as the third trimester if justified.[4]

Treatment management of associated symptoms and/or complications includes:

• Hydrocephalus: A condition that presents commonly in patients with hydranencephaly. To treat the hydrocephalus, placement of a ventriculoperitoneal or ventriculoatrial shunt system to reduce the intracranial pressure can be performed.
• Anti-epileptic drugs: Seizures are one of the most common conditions that patients with hydranencephaly present with.
• Tracheostomy and/or mechanical ventilation: Used for patients with respiratory failure.
• Physical therapy: Hydranencephalic patients have poor psychomotor development and need physical and occupational therapy.
• Nutritional intervention: This will improve the outcome.

Even though shunts are the most commonly used treatment for hydrocephalus, there are many complications associated with them. They have to be frequently revised due to malfunctions and have a high rate of infections, especially in the pediatric population. Approximately 25% to 40% of pediatric patients with a shunt will undergo revision in 1 year, and 81% will require revision in the next 12 years.[16] Additionally, the multiple neurosurgical interventions and costs associated with them are an issue of concern.[16] Other procedures have been proposed to treat and manage hydrocephalus as an alternative to shunts.[16]  Endoscopic choroid plexus coagulation (ECPC) is an alternative to treat rapidly enlarging heads in patients with hydranencephaly due to hydrocephalus.[16][17] Multiple studies have reported better outcomes in patients treated with ECPC than in those treated with shunts with a success rate of 50 to 80%.[16][17][18] This success rate is high enough to propose that ECPC could be used as the standard of care in the treatment of hydrocephalus or an enlarging head in an infant diagnosed with hydranencephaly.[18]

Nonetheless, it is clearly noted that ECPC can have better results in treating high CSF production only in patients with hydranencephaly and not in other forms of hydrocephalus.[16][18] This is because patients with hydranencephaly have certain anatomical characteristics that make ECPC possible, such as the lack of septum pellucidum (lack of hemispheric separation), which allows easy access to bilateral choroid plexuses, and the lack of brain parenchyma which makes the choroid plexus the principal production area of CSF.[16] A complication associated with ECPC is arachnoid collapse. It occurs when the dura is opened to pass the endoscope, which liberates the intracranial pressure and leads to arachnoid collapse with the inability to coagulate the choroid plexuses.[16]

Differential Diagnosis

Hydranencephaly has some unique findings on imaging and ancillary tests that help to differentiate it from other conditions such as severe-extreme hydrocephalus, holoprosencephaly (especially the alobar holoprosencephaly type), severe open schizencephaly, and anencephaly.[4][5][15][5]

• Hydrocephalus (severe-extreme): This can occur due to multiple etiologies. The cortical mantle is preserved. There is the presence of the third ventricle, abnormal head circumference at birth, full and bulging fontanelles, and a normal vascular study. There is significant clinical and radiographic improvement after shunt placement, which can improve prognosis.
• Holoprosencephaly (alobar): It is the most severe form of holoprosencephaly. This is a condition that occurs due to a congenital cerebral anomaly that results due to absent or incomplete division of the forebrain. In this form of holoprosencephaly, there is a partial fusion of the thalami, and the falx is missing. These patients present with facial anomalies and small head circumference.
• Schizencephaly (severe open): This occurs due to an abnormality in the migration of neurons, leaving clefts lined with abnormal gray matter, described as polymicrogyria. There is a thinning but preservation of the cortical mantle, which is absent in hydranencephaly.
• Anencephaly: This is caused by a neural tube obstruction disorder and the classical finding will be a defect in the skull as well as in the brain parenchyma.

Prognosis

Unfortunately, there is no cure for hydranencephaly, and treatment is symptomatic and supportive.[4] Most patients with hydranencephaly die in-utero. For those patients that do survive, the prognosis is poor, and the majority of patients die during the 1st year of life due to complications. There are reports of patients that do survive and have reached up to 32 years of age.[5]

The survival of patients with hydranencephaly is dependent on the integrity of the brainstem, which regulates vital aspects such as cardiorespiratory functions and temperature regulation. Those few patients described in the literature that survive past the 1st year of life do not improve after shunt placement. The neurological function remains stable during their lifetime. There is limited use of hands and communication responses; however, some patients can use some words.[4][5][16][19]

Complications

Complications associated with hydranencephaly are frequently the cause of death of patients that survive.  

• Developmental delay
• Seizures (including drug-resistant seizures) 
• Spastic diplegia
• Severe growth failure 
• Infections (respiratory infections are the most common) 
• Cerebral palsy
• Irritability
• Respiratory distress
• Prolonged mechanical ventilation
• Gastroesophageal reflux
• Emotional, psychological, and economic implications for the parents

Consultations

It is important to have a wide interprofessional team involved in the care of a patient with hydranencephaly. 

• Neonatologist/pediatrician
• Neurosurgeon
• Neurologist
• Radiologist
• Obstetrician
• Intensivist
• Physical therapy and rehabilitation
• Nutritionist 
• Social worker
• Psychologist/psychiatrist

Deterrence and Patient Education

The emotional toll of having a child with hydranencephaly can be profound. There is no prevention of this disease except for those cases with exposure to toxins such as cocaine, smoking, and sodium valproate. Avoidance of these toxins should be encouraged. Counseling and support are necessary for the parents, especially to educate them about the diagnosis and prognosis. Psychologist and psychiatrist interactions may be needed.

Pearls and Other Issues

It is extremely important to differentiate between hydranencephaly and severe-extreme hydrocephalus. Both disorders can present similarly, but prognosis and management are very different. A patient with severe-extreme hydrocephalus improves significantly clinically and radiographically after treatment, while those with hydranencephaly do not. If treatment is delayed, it can lead to catastrophic outcomes.

Enhancing Healthcare Team Outcomes

While the neonatologist is almost always involved in the care of patients with hydranencephaly, it is important to consult with an interprofessional team of specialists that include an obstetrician, neurologist, physiatrist, neurosurgeon, and social worker. The nurses are also vital members of the interprofessional group as they will assist patients with their daily care, while social workers assist with the education of the family.

The radiologist also plays a vital role in determining the diagnosis. The outcomes of a patient with hydranencephaly depend on its cause and the severity of the disease. To improve outcomes, prompt consultation with an interprofessional group of specialists is recommended.