Megalencephaly

Definition

Megalencephaly (also called macrencephaly) describes an enlarged brain whose weight exceeds the mean (the average weight for that age and sex) by at least 2.5 standard deviations (a statistical measure of variation). Megalencephaly may also be defined in terms of volume rather than weight. Hemimegalencephaly (or unilateral megalencephaly) is a related condition in which brain enlargement occurs in one hemisphere (half) of the brain.

Description

A person with megalencephaly has a large, heavy brain. In general, a brain that weighs more than 1600 grams (about 3.5 pounds) is considered megalencephalic. The heaviest brain on record weighed 2850 grams (about 6.3 pounds). Macrocephaly, a related condition, refers to an abnormally large head. Macrocephaly may be due to megalencephaly or other causes such as hydrocephalus (an excess accumulation of fluid in the brain), and brain edema. Megalencephaly may be an isolated finding in an otherwise normal individual or it can occur in association with neurological problems (such as seizures or mental retardation ) and/or somatic abnormalities (physical problems or birth defects of the body). Dysmorphic facial features (abnormal shape, position or size of facial features) may also be observed in an affected individual.

According to the National Institute of Neurological Disorders and Stroke (NINDS), megalencephaly is one of the cephalic disorders, congenital conditions due to damage to or abnormal development of the nervous system. There have been various attempts to classify megalencephaly into subcategories based on etiology (cause) and/or pathology (the condition of the brain tissue and cells). Dekaban and Sakurgawa (1977) proposed three main categories: primary megalencephaly, secondary megalencephaly, and hemimegalencephaly. DeMyer (1986) proposed two main categories: anatomic and metabolic. Gooskens and others (1988) modified these classifications and added a third category: dynamic megalencephaly. The existence of different classification systems highlights the inherent difficulty in categorizing a condition that has a wide range of causes and associated pathology.

Demographics

The incidence of megalencephaly is estimated at between 2% and 6%. There is a preponderance of affected males; megalencephaly affects males three to four times more often than it does females. Among individuals with macrocephaly, estimates of megalencephaly are between 10 and 30%. Hemimegalencephaly is a rare condition and occurs less frequently than megalencephaly.

Causes and symptoms

Both genetic and non-genetic factors may produce megalencephaly. Most often, megalencephaly is a familial trait that occurs without extraneural (outside the brain) findings. Familial megalencephaly may occur as an auto-somal dominant (more common) or autosomal recessive condition. The autosomal recessive form is more likely than the autosomal dominant form to result in mental retardation. Other genetic causes for megalencephaly include single gene disorders such as Sotos syndrome (an overgrowth syndrome), neurofibromatosis (a neurocutaneous syndrome), and Alexander disease (a leukodystrophy ); or a chromosome abnormality such as Klinefelter syndrome. Non-genetic factors such as a transient disorder of cerebral spinal fluid may also contribute to the development of megalencephaly. Finally, megalencephaly can be idiopathic (due to unknown causes).

The cells that make up the brain (neurons and other supporting cells) form during the second to fourth months of pregnancy. Though the precise mechanisms behind megalencephaly at the cellular level are not fully understood, it is thought that the condition results from an increased number of cells, an increased size of cells, or accumulation of a metabolic byproduct or abnormal substance due to an inborn error of metabolism. It is possible that more than one of these processes may explain megalencephaly in a given individual.

There is variability in age of onset, symptoms present, rate of progression, and severity of megalencephaly. The disorder typically presents as a large head circumference (distance around the head) either prenatally (before birth), at birth, or within the first few years of life. The head circumference may increase rapidly in the span of a few months or may progress slowly over a longer period of time. Head shape may be abnormal and skull abnormalities such as widened or split sutures (fibrous joints between the bones of the head) may occur. There may also be increased cranial pressure and bulging fontanels (the membrane covered spaces at the juncture of an infant's cranial bones which later harden).

From a neurological standpoint, the clinical picture of megalencephaly varies widely. Manifestations may range from normal intellect, as with case of benign familial megalencephaly, to severe mental retardation and seizures, as with Alexander disease, an inherited leukodystrophy (disease of the brain's white matter). Neurological symptoms that may be present or develop in a person with megalencephaly include:

• delay of motor milestones such as holding up head, rolling over, or sitting
• mental retardation
• speech delay
• poor muscle tone
• body asymmetry
• paralysis of one or both sides of the body
• poor coordination
• involuntary movements
• visual disturbances

Brain abnormalities that may be seen in individuals with megalencephaly include:

• gyral abnormalities
• neuronal heterotopias
• corpus callosum dysgenesis
• myelum dysplasia
• abnormal or an excess amount of neurons
• abnormal or an excess amount of glia cells

Diagnosis

A diagnosis of megalencephaly is based on clinical findings and results of brain imaging studies. Since megalencephaly can be a benign condition, there may well be many individuals who never come to medical attention. Though no longer used as a primary means of diagnosing megalencephaly, an autopsy may provide additional evidence to support this diagnosis. The evaluation of a patient with suspected megalencephaly will usually consist of questions about medical history and family history, a physical exam that includes head measurements, and a developmental and/or neurological exam. It may be necessary to obtain head circumference measurements for first-degree relatives (parents, siblings, children). Depending upon the history and clinical findings, a physician may recommend imaging studies such as CT (computed tomography) scan or MRI (magnetic resonance imaging ). Findings on CT scan or MRI consistent with a diagnosis of megalencephaly are an enlarged brain with normal-sized ventricles and subarachnoid spaces. The volume (size) of the brain may be calculated or estimated using measurements from the CT or MRI. A patient with megalencephaly may be referred to specialists in neurology or genetics for further evaluation. Laboratory testing for a genetic condition or chromosome abnormality may also be performed.

Treatment

There is no specific cure for megalencephaly. Management of this condition largely depends upon the presence and severity of associated neurological and physical problems. In cases of benign familial megalencephaly, additional management beyond routine health care maintenance may consist of periodic head measurements and patient education about the inheritance and benign nature of the condition. For patients with neurological and/or physical problems, management may include anti-epileptic drugs for seizures, treatment of medical complications related to the underlying syndrome, and rehabilitation for neurological problems such as speech delay, poor muscle tone, and poor coordination. Placement in a residential care facility may be necessary for those cases in which megalencephaly is accompanied by severe mental retardation or uncontrollable seizures.

Treatment team

The types of professionals involved in the care of patients is highly individualized because the severity of symptoms varies widely from patient to patient. For patients with associated neurological and/or physical problems, the treatment team may include specialists in neonatology, neurology, radiology, orthopedics, rehabilitation, and genetics. Genetic counseling may be helpful to the patient and family, especially at the time of diagnosis. Participation in a support group may also be beneficial to those families adversely affected by megalencephaly.

Recovery and rehabilitation

The optimal remedial strategies for individuals with megalencephaly depend upon the presence and severity of associated neurological and physical problems. Interventions such as speech, physical, and occupational therapy may be indicated for individuals with megalencephaly. Early intervention services for young children and special education or other means of educational support for school-aged children may be recommended if developmental delays, learning disabilities, or other barriers to learning are present. The goal of these therapies is to maximize the patient's success in school, work, and life in general. A child with megalencephaly may be eligible to have an Individual Education Plan (IEP). An IEP provides a framework from which administrators, teachers, and parents can meet the educational needs of a child with learning disabilities. Depending upon severity of symptoms and the degree of learning difficulties, some children with megalencephaly may be best served by special education classes or a private educational setting.

Clinical trials

As of 2004, there were no active clinical trials specifically designed to study megalencephaly. Patients with underlying syndromes that produce megalencephaly may be candidates for clinical trials that relate to that particular syndrome. For more information, interested individuals may search for that specific condition (for example, neurofibromatosis) at www.clinicaltrails.gov.

Prognosis

The prognosis for megalencephaly varies according to the presence and severity of associated problems such as intractable seizures, paralysis, and mental retardation. Hemimegalencephaly is often associated with severe seizures, hemiparesis (paralysis of one side of the body), and mental retardation and as such, it carries a poor prognosis. In the case of a fetus diagnosed with megalencephaly, prediction of outcome remains imprecise.

Resources

BOOKS

Greer, Melvin. "Structural Malformations," Chapter 78. In Merritt's Textbook of Neurology, 10th edition, edited by L. P. Rowland. Baltimore, MD: Williams and Wilkins, 2000.

Graham, D. I., and P. L. Lantos, eds. Greenfield's Neuropathology, volume I, 7th edition. London: Arnold, 2002.

Parker, James N., and Philip M. Parker, eds. The Official Parent's Sourcebook on Alexander Disease: A Revised and Updated Directory for the Internet Age. San Diego, CA: ICON Health Publications, 2003.

PERIODICALS

Bodensteiner, J. B. and E. O. Chung. "Macrocrania and megalencephaly in the neonate." Seminars on Neurology 13 (March 1993): 84–91.

Cutting, L. E., K. L. Cooper, C. W. Koth, S. H. Mostofsky, W.R. Kates, M. B. Denckla, and W. E. Kaufmann. "Megalencephaly in NF1: predominantly white matter contribution and mitigation by ADHD." Neurology 59 (November 2002): 1388–94.

DeMyer, W. "Megalencephaly: types, clinical syndromes and management." Pediatric Neurology 2 (1986): 321–28.

Gooskens, R. H. J. M., J. Willemse, J. B. Bijlsma, and P. Hanlo. "Megalencephaly: Definition and classification." Brain and Development 10 (1988): 1–7.

Johnson, A. B., and M. Brenner. "Alexander's disease: clinical, pathologic, and genetic features." Journal of Child Neurology 18 (September 2003): 625–32.

Singhal, B. S., J. R. Gorospe, and S. Naidu. "Megalencephalic leukoencephalopathy with subcortical cysts." Journal of Child Neurology 18 (September 2003): 646–52.

WEBSITES

The National Institute of Neurological Disorders and Stroke (NINDS). Megalencephaly Information Page. <http://www.ninds.nih.gov/health_and_medical/disorders/megalencephaly.htm>.

The National Institute of Neurological Disorders and Stroke (NINDS). Cephalic Disorders Fact Sheet. <http://www.ninds.nih.gov/health_and_medical/pubs/cephalic_disorders.htm>.

Online Mendelian Inheritance In Man (OMIM). Megalencephaly. <http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=155350>.

ORGANIZATIONS

National Institute of Child Health and Human Development (NICHD) Information Resource Center. P. O. Box 3006, Rockville, MD 20847. (301) 496-7101 or (800) 370-2943. NICHDInformationResourceCenter@mail.nih.gov. <http://www.nichd.nih.gov>.

National Institute of Neurological Disorders and Stroke (NINDS, Brain Resources and Information Network (BRAIN). P. O. Box 5801, Bethesda, MD. (800) 352-9424. <http://www.ninds.nih.gov>.

National Organization for Rare Disorders (NORD). PO Box 1968, 55 Kensonia Avenue, Danbury, CT 06813. (203) 744-0100 or 800-999-NORD (6673); Fax: (203) 798-2291. orphan@rarediseases.org. <http://www.rarediseases.org>.

Dawn J. Cardeiro, MS, CGC