Macrocephaly

Macrocephaly is defined as head circumference more than two standard deviations (SD) above the mean value for a given age and gender.[1] It has to be differentiated from megalencephaly, which is defined as increase in the size of the brain parenchyma. Head circumference is measured to monitor head growth in infants and children. It is also known as occipitofrontal circumference (OFC) and it denotes the size of the cranium. Macrocephaly can be the first manifestation of various congenital and acquired neurologic conditions or may be just a familial trait.[2] The images below show an infant with this condition.

A 1-year-old boy with macrocephaly. The image illustrates the increased head circumference (large head).

A 1-year-old boy with macrocephaly. The image illustrates the increased head circumference (large head).

A 1-year-old boy with macrocephaly. The image illustrates the increased head circumference (large head).

Macrocephaly can result from enlargement of the skull bones or an increase in the volume of the intracranial structures like cerebrospinal fluid, blood, or the brain parenchyma itself (megalencephaly). It may be secondary to raised intracranial pressure or space-occupying lesions. It can also be a feature of various congenital syndromes and is then referred to as syndromic macrocephaly. The pathogenesis is therefore cause-dependent. 

Macrocephaly is a relatively rare condition but has multiple etiologies, therefore the incidence and prevalence has not been documented by many studies. However, one community-based study in Israel quoted a prevalence of 1.4%.[3] There is no gender or racial predisposition.

The outcome and prognosis depends on the cause. The prognosis is quite favorable in children with benign familial macrocephaly.

The severity of neurologic dysfunction, cognitive decline, and physical handicap determine the degree of dependency of the child. Both parents and teachers have to be educated accordingly to address the problems of such children. All aspects of physical, mental, social, and behavioral caregiving should be taken care of.   

The etiology of macrocephaly is diverse.[4] The most common cause is benign familial macrocephaly characterized by enlargement of the subarachnoid spaces and accounts for almost 50% of cases.

Other causes are described below.

Enlargement of skull bones

1. Hyperostosis cranii - associated with disorders such as osteogenesis imperfecta, achondroplasia, and osteopetrosis
2. Secondary enlargement due to bone marrow expansion - as seen in thalassemia major

Increase in volume of cerebrospinal fluid

1. Hydrocephalus
2. Choroid plexus papilloma
3. Benign familial macrocephaly

Megalencephaly

1. Leukodystrophies - Canavan disease, Alexander disease, megalencephalic leukoencephalopathy with subcortical cysts
2. Lysosomal storage disorders - Tay-sachs, mucopolysaccharoidosis, gangliosidosis
3. Neurocutaneous disroders - Tuberous sclerosis, Sturge-weber syndrome, neurofibromatosis, Gorlin syndrome
4. Autism spectrum disorder
5. Other syndromes - Fragile X syndrome, Cowden syndrome, Sotos syndrome

Increased intracranial pressure (ICP)

1. CNS infections
2. Pseudotumor cerebri
3. Subdural collections including hygromas

Mass lesions and increase in volume of blood

1. Tumor
2. Intraventricular hemorrhage, subdural hematoma, arteriovenous malformation

The presentation varies depending upon the underlying etiology. The evaluation includes a detailed history and thorough physical examination of the child and parents. Depending upon the clinical findings, further assessment may accordingly be performed. History should be assiduously sought. The following aspects must be assessed:

• Age at the onset of the disease
• Birth history - with information about the birth weight, length, and head size
• History of development and growth - with special attention paid to the chronology of attainment of milestones; and subsequently regression, if any. Time of closure of fontanels should also be established.
• History of other associated features (e.g., headache, vomiting, seizures, cognitive decline)
• History of fever, central nervous system infection, head injury, or intracranial hemorrhage
• Family history - metabolic disorders, neurocutaneous disorders, macrocephaly, and consanguineous marriages

A detailed and methodical approach is necessary for the examination of these children.

General physical examination

The physical exam should assess for the following:

• Dysmorphic facial features
• Facial angiofibromas
• Port wine stain
• Periungual fibromas
• Ashleaf macules
• Shagreen patches
• Cataracts
• Retinal hemartomas
• Papilledema
• Optic atrophy
• Assessment of the fontanels in infants younger than two years of age
• Transillumination of the skull in infants younger than one year of age
• Skeletal deformities.
• Weight and length assessment - The child's weight and length must be measured on each visit and values should be plotted on standard curves to monitor growth.

Measurement of head size or occipitofrontal circumference (OFC)

The OFC is measured with a measuring tape completely encircling the head positioned over the widest circumference, including an area 1 to 2 cm above the root of the nose anteriorly and posteriorly the most prominent portion of the occiput; with the ears avoided. The measured value should be plotted on a standard curve to monitor the change in head size over time.

Various gender-specific growth charts have been published, but the Centers for Disease Control (CDC) currently recommends that children in the United States between the ages of 0 and 2 years old are tracked with the World Health Organization (WHO) growth charts, and with the CDC growth charts after children turn 2 years old. Minor differences do exist between the two charts. Clinicians can easily tell the difference because charts from WHO data tend to stop at 24 months of age, whereas the charts from CDC data extend to 36 months of age.[5, 6]

Neurologic assessment

A neurologic exam should assess the following:

• Cognitive level 
• Tone - hypotonia, spasticity
• Deep tendon reflexes - may be exaggerated in leukodystrophies and other central nervous system disorders
• Plantar responses

Systemic examination

A systemic exam should assess the following:

• Hepatosplenomegaly - associated with storage diseases
• Congenital heart disease

Investigation modalities for the evaluation of macrocephaly are primarily radiology based.[7] The main purpose is to detect intracranial abnormalities. The options that may be considered include skull radiography (antero-posterior and lateral views) and ultrasonography of the skull (before closure of anterior fontanel). Computed tomography (CT) scan of the head or magnetic resonance imaging (MRI) of the head should be considered in macrocephalic children with neurodevelopmental abnormalities or features of raised intracranial pressure. Typically, CT scans are more readily accessible and can be performed without sedation, so are most appropriate to assess for an acute process. MRIs provide greater detail, in particular of the posterior fossa, so should be considered if time allows.

Skull radiography 

Radiographs of the skull can be used to measure and document the head size. In addition, they may reveal typical findings in cases of skeletal dysplasias. Sometimes features associated with increased intracranial pressure may be evident. These include “Beaten Copper cranium”[8] with prominence of convolutional markings on the inner table of the cranial vault, thinning of the cranial bones, widening and separation of sutures, and pressure atrophy of the skull base with erosion and enlargement of the sella turcica (see images below).

Lateral view on skull radiograph of a 1-year-old boy with macrocephaly. The increased antero-posterior diameter can be appreciated.

Antero-posterior view on skull radiograph of a 1-year-old boy with macrocephaly.

Antero-posterior and lateral views on skull radiographs of a 1-year-old boy with macrocephaly.

Head ultrasound (HUS) 

This technique is fairly simple and useful in infants with macrocephaly with an open anterior fontanel, provided the infants have a normal neurological examination and no features to suggest raised intracranial pressure.[9] HUS may reveal prominent ventricles and enlargement of subarachnoid space. Once intracranial pathology is excluded, these infants require only close neurological follow up.

Computed tomography

CT scan of the head is important in cases of hydrocephalus. It is also useful in syndromic macrocephaly cases like Sturge weber syndrome and tuberous sclerosis, as calcifications are seen well on CT scan. (See images below.)

Noncontrast CT scan of brain of a 2-year-old boy showing gross hydrocephalus with paper thin brain tissue (coronal view).

Noncontrast CT scan of brain of a 2-year-old boy showing gross hydrocephalus with paper thin brain tissue (coronal view).

Noncontrast CT scan of brain of a 2-year-old boy showing gross hydrocephalus with paper thin brain tissue (coronal view).

Noncontrast CT scan of brain of a 2-year-old boy showing gross hydrocephalus with paper thin brain tissue (coronal view).

Magnetic resonance imaging

MRI of the brain not only defines the size of the ventricular chain in hydrocephalus, it can also delineate intracranial mass lesions and vascular malformations as well as identify white matter changes in cases of leukodystrophies. It can also distinguish cases of enlargement of the subarachnoid space in benign familial macrocephaly from subdural hygromas and hamartomas.

Other tests that may prove helfpul for diagnosis include the following:

• Molecular genetic testing
• Metabolic tests
• Tests for other associations like electrocardiogram, echocardiography, ultrasound of the abdomen, and skeletal survey.

The management is variable depending upon the etiology of macrocephaly.

Benign familial macrocephaly does not necessitate treatment and children mostly remain asymptomatic. Periodic monitoring of head size is sufficient in these cases along with regular monitoring for physical growth and neurologic development.

Macrocephalic children with epilepsy require therapy with appropriate antiepileptic medication.

Neurosurgical intervention may be warranted in children with hydrocephalus and consequent symptoms of increased intracranial pressure. Various procedures may be considered for drainage of CSF in order to reduce the fluid volume including placement of a extraventricular drain (EVD) or a ventriculoperitoneal (VP) shunt (see image below).[10]

Ventriculoperitoneal shunt in situ.

Another surgery reported in the literature is complete reconstruction of the skull in children with grossly deformed skull architecture. It has been tried in a case of macrocephaly due to hydrocephalus.[11]

Consultation with any of the following may prove helpful:

• Pediatrician
• Geneticist
• Pediatric neurologist
• Pediatric neurosurgeon

It is recommended to measure and plot the head size monthly for six months to ascertain the growth curve of the child and to compare it to the normal curve. Physical and neurologic examination should be carried out regularly. Neuroimaging is not routinely recommended unless there is abnormal or rapid increase in head size or there is motor, cognitive, or growth retardation or loss of milestones.

Pharmacotherapy may be necessary to address other symptoms that may be seen in conditions involving macrocephaly, with goals of reducing morbidity and preventing complications. For instance, antiseizure medication may be required in children with macrocephaly and seizures. The choice of medication depends on the seizure type. 

Class Summary

These agents prevent seizure recurrence and terminate clinical and electrical seizure activity.

Valproic acid (Depacon, Depakene, Stavzor)

Valproic acid can be instituted in macrocephalic children with recurrent generalized seizures. It is easily available, inexpensive, and often confers good seizure control. Other drugs which are "broad-spectrum," effective in treating primary generalized or focal-onset seizures, include levetiracetam, topiramate, lamotrigine. 

Levetiracetam (Keppra, Keppra XR, Spritam, Roweepra)

The mechanism of action of levetiracetam is unknown. It is indicated for primary generalized tonic-clonic seizures in adults and children aged 6 years or older, as well as for use in juvenile myoclonic epilepsy and for partial seizures.

Carbamazepine (Carbatrol, Epitol, Equetro, Tegretol, Tegretol-XR)

Carbamazepine is a tricyclic compound extensively metabolized to its active metabolite, carbamazepine-epoxide. This agent markedly induces its own metabolism and is highly bound to plasma proteins. It is effective towards preventing focal-onset seizures, and may exacerbate primary generalized seizures.

Topiramate (Qudexy XR, Topamax, Trokendi XR)

An antiepileptic drug with a broad spectrum of antiepileptic activity, topiramate is approved for generalized tonic-clonic seizures. It has multiple mechanisms of action, including state-dependent sodium channel blocking action; it also potentiates inhibitory activity of the neurotransmitter GABA. It may block glutamate activity and also is a carbonic anhydrase inhibitor.